A. C. Carpenter and R. Bosselut, Decision checkpoints in the thymus, Nature Immunology, vol.20, issue.8, pp.666-673, 2010.
DOI : 10.4049/jimmunol.181.5.2980

K. A. Hogquist and S. C. Jameson, The self-obsession of T cells: how TCR signaling thresholds affect fate 'decisions' and effector function, Nature Immunology, vol.340, issue.9, pp.815-823, 2014.
DOI : 10.1084/jem.20122528

R. W. Wilkinson, G. Anderson, J. J. Owen, and E. J. Jenkinson, Positive selection of thymocytes involves sustained interactions with the thymic microenvironment, J Immunol, vol.155, pp.5234-5240, 1995.

R. J. And-notes-1, J. P. Mandl, N. Monteiro, R. N. Vrisekoop, and . Germain, T cell-positive selection uses self-ligand binding strength to optimize repertoire recognition of foreign antigens, Immunity, vol.38, pp.263-274, 2013.

G. Fu, S. Vallée, V. Rybakin, M. V. Mcguire, J. Ampudia et al., Themis controls thymocyte selection through regulation of T cell antigen receptor???mediated signaling, Nature Immunology, vol.15, issue.8, pp.848-856, 2009.
DOI : 10.4049/jimmunol.167.9.4966

A. L. Johnson, L. Aravind, N. Shulzhenko, A. Morgun, S. Choi et al., Themis is a member of a new metazoan gene family and is required for the completion of thymocyte positive selection, Nature Immunology, vol.34, issue.8, pp.831-839, 2009.
DOI : 10.4049/jimmunol.167.4.2030

K. Kakugawa, T. Yasuda, I. Miura, A. Kobayashi, H. Fukiage et al., A Novel Gene Essential for the Development of Single Positive Thymocytes, Molecular and Cellular Biology, vol.29, issue.18, pp.5128-5135, 2009.
DOI : 10.1128/MCB.00793-09

R. Lesourne, S. Uehara, J. Lee, K. Song, L. Li et al., Themis, a T cell???specific protein important for late thymocyte development, Nature Immunology, vol.5, issue.8, pp.840-847, 2009.
DOI : 10.1016/S1525-1578(10)60455-2

M. S. Patrick, H. Oda, K. Hayakawa, Y. Sato, K. Eshima et al., Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes, Proceedings of the National Academy of Sciences, vol.29, issue.18, pp.16345-16350, 2009.
DOI : 10.1128/MCB.00793-09

W. Paster, C. Brockmeyer, G. Fu, P. C. Simister, B. De-wet et al., GRB2-Mediated Recruitment of THEMIS to LAT Is Essential for Thymocyte Development, The Journal of Immunology, vol.190, issue.7, pp.3749-3756, 2013.
DOI : 10.4049/jimmunol.1203389

R. Lesourne, E. Zvezdova, K. Song, D. El-khoury, S. Uehara et al., Interchangeability of Themis1 and Themis2 in Thymocyte Development Reveals Two Related Proteins with Conserved Molecular Function, The Journal of Immunology, vol.189, issue.3, pp.1154-1161, 2012.
DOI : 10.4049/jimmunol.1200123

G. Fu, J. Casas, S. Rigaud, V. Rybakin, F. Lambolez et al., Themis sets the signal threshold for positive and negative selection in T-cell development, Nature, vol.167, issue.7480, pp.441-445, 2013.
DOI : 10.1084/jem.20092170

W. Paster, A. M. Bruger, K. Katsch, C. Grégoire, R. Roncagalli et al., complex promotes T-cell survival, EMBO J, vol.34, pp.1-393, 2015.

K. G. Johnson, F. G. Leroy, L. K. Borysiewicz, and R. J. Matthews, TCR signaling thresholds regulating T cell development and activation are dependent upon SHP-1, J. Immunol, vol.162, pp.3802-3813, 1999.

D. R. Plas, C. B. Williams, G. J. Kersh, L. S. White, J. M. White et al., Cutting edge: The tyrosine phosphatase SHP-1 regulates thymocyte positive selection, J. Immunol, vol.162, pp.5680-5684, 1999.

J. Zhang, A. Somani, D. Yuen, Y. Yang, P. E. Love et al., Involvement of the SHP-1 tyrosine phosphatase in regulation of T cell selection, J. Immunol, vol.163, pp.3012-3021, 1999.

C. C. Fowler, L. I. Pao, J. N. Blattman, and P. D. Greenberg, SHP-1 in T Cells Limits the Production of CD8 Effector Cells without Impacting the Formation of Long-Lived Central Memory Cells, The Journal of Immunology, vol.185, issue.6, pp.3256-3267, 2010.
DOI : 10.4049/jimmunol.1001362

A. E. Moran, K. L. Holzapfel, Y. Xing, N. R. Cunningham, J. S. Maltzman et al., and iNKT cell development demonstrated by a novel fluorescent reporter mouse, The Journal of Experimental Medicine, vol.208, issue.6, pp.1279-1289, 2011.
DOI : 10.1126/science.1103440

R. M. Siegel, M. Katsumata, T. Miyashita, D. C. Louie, M. I. Greene et al., Inhibition of thymocyte apoptosis and negative antigenic selection in bcl-2 transgenic mice., Proceedings of the National Academy of Sciences, vol.89, issue.15, pp.7003-7007, 1992.
DOI : 10.1073/pnas.89.15.7003

O. Williams, T. Norton, M. Halligey, D. Kioussis, and H. J. Brady, The Action of Bax and Bcl-2 on T Cell Selection, The Journal of Experimental Medicine, vol.14, issue.6, pp.1125-1133, 1998.
DOI : 10.1074/jbc.272.46.29347

L. F. Reynolds, L. A. Smyth, T. Norton, N. Freshney, J. Downward et al., Vav1 Transduces T Cell Receptor Signals to the Activation of Phospholipase C-??1 via Phosphoinositide 3-Kinase-dependent and -independent Pathways, The Journal of Experimental Medicine, vol.2, issue.9, pp.1103-1114, 2002.
DOI : 10.1186/1471-2172-2-3

J. Wu, D. G. Motto, G. A. Koretzky, and A. Weiss, Vav and SLP-76 Interact and Functionally Cooperate in IL-2 Gene Activation, Immunity, vol.4, issue.6, pp.593-602, 1996.
DOI : 10.1016/S1074-7613(00)80485-9

B. Aghazadeh, W. E. Lowry, X. Huang, and M. K. Rosen, Structural Basis for Relief of Autoinhibition of the Dbl Homology Domain of Proto-Oncogene Vav by Tyrosine Phosphorylation, Cell, vol.102, issue.5, pp.625-633, 2000.
DOI : 10.1016/S0092-8674(00)00085-4

S. P. Hehner, T. G. Hofmann, O. Dienz, W. Dröge, and M. L. Schmitz, Tyrosine-phosphorylated Vav1 as a Point of Integration for T-cell Receptor- and CD28-mediated Activation of JNK, p38, and Interleukin-2 Transcription, Journal of Biological Chemistry, vol.19, issue.24, pp.18160-18171, 2000.
DOI : 10.1126/science.282.5397.2266

K. V. Salojin, J. Zhang, and T. L. Delovitch, TCR and CD28 are coupled via ZAP-70 to the activation of the Vav/Rac-1-/PAK-1/p38 MAPK signaling pathway, J. Immunol, vol.163, pp.844-853, 1999.

M. Deckert, S. Tartare-deckert, C. Couture, T. Mustelin, and A. Altman, Functional and Physical Interactions of Syk Family Kinases with the Vav Proto-Oncogene Product, Immunity, vol.5, issue.6, pp.591-604, 1996.
DOI : 10.1016/S1074-7613(00)80273-3

M. Nishida, K. Nagata, Y. Hachimori, M. Horiuchi, K. Ogura et al., Novel recognition mode between Vav and Grb2 SH3 domains, The EMBO Journal, vol.20, issue.12, pp.2995-3007, 2001.
DOI : 10.1093/emboj/20.12.2995

Z. Ye and D. Baltimore, Binding of Vav to Grb2 through dimerization of Src homology 3 domains., Proceedings of the National Academy of Sciences, vol.91, issue.26, pp.12629-12633, 1994.
DOI : 10.1073/pnas.91.26.12629

W. Zhang, R. P. Trible, M. Zhu, S. K. Liu, C. J. Mcglade et al., Association of Grb2, Gads, and Phospholipase C-??1 with Phosphorylated LAT Tyrosine Residues, Journal of Biological Chemistry, vol.12, issue.30, pp.23355-23361, 2000.
DOI : 10.1128/MCB.12.7.3305

N. Fang and G. A. Koretzky, SLP-76 and Vav Function in Separate, but Overlapping Pathways to Augment Interleukin-2 Promoter Activity, Journal of Biological Chemistry, vol.17, issue.23, pp.16206-16212, 1999.
DOI : 10.1006/smim.1998.0124

H. Asada, N. Ishii, Y. Sasaki, K. Endo, H. Kasai et al., Grf40, A Novel Grb2 Family Member, Is Involved in T Cell Signaling through Interaction with SLP-76 and LAT, The Journal of Experimental Medicine, vol.27, issue.9, pp.1383-1390, 1999.
DOI : 10.1038/sj.onc.1202337

S. K. Liu, N. Fang, G. A. Koretzky, and C. J. Mcglade, The hematopoietic-specific adaptor protein Gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors, Current Biology, vol.9, issue.2, pp.67-75, 1999.
DOI : 10.1016/S0960-9822(99)80017-7

H. S. Azzam, A. Grinberg, K. Lui, H. Shen, E. W. Shores et al., CD5 Expression Is Developmentally Regulated By T Cell Receptor (TCR) Signals and TCR Avidity, The Journal of Experimental Medicine, vol.154, issue.12, pp.2301-2311, 1998.
DOI : 10.1146/annurev.iy.12.040194.003331

Q. Gong, A. M. Cheng, A. M. Akk, J. Alberola-ila, G. Gong et al., Disruption of T cell signaling networks and development by Grb2 haploid insufficiency, Nature Immunology, vol.8, issue.1, pp.29-36, 2001.
DOI : 10.1128/MCB.8.8.3235

I. K. Jang, J. Zhang, Y. J. Chiang, H. K. Kole, D. G. Cronshaw et al., Grb2 functions at the top of the T-cell antigen receptor-induced tyrosine kinase cascade to control thymic selection, Proceedings of the National Academy of Sciences, vol.29, issue.3, pp.10620-10625, 2010.
DOI : 10.1038/ng750

K. Pfrepper, A. Marie-cardine, L. Simeoni, Y. Kuramitsu, A. Leo et al., Structural and functional dissection of the cytoplasmic domain of the transmembrane adaptor protein SIT (SHP2-interacting transmembrane adaptor protein), European Journal of Immunology, vol.274, issue.6, pp.1825-1836, 2001.
DOI : 10.1074/jbc.274.17.12183

L. Simeoni, V. Posevitz, U. Kölsch, I. Meinert, E. Bruyns et al., The Transmembrane Adapter Protein SIT Regulates Thymic Development and Peripheral T-Cell Functions, Molecular and Cellular Biology, vol.25, issue.17, pp.7557-7568, 2005.
DOI : 10.1128/MCB.25.17.7557-7568.2005

A. K. Chakraborty, J. Das, J. Zikherman, M. Yang, C. C. Govern et al., Molecular Origin and Functional Consequences of Digital Signaling and Hysteresis During Ras Activation in Lymphocytes, Science Signaling, vol.2, issue.66, p.2, 2009.
DOI : 10.1126/scisignal.266pt2

J. Das, M. Ho, J. Zikherman, C. Govern, M. Yang et al., Digital Signaling and Hysteresis Characterize Ras Activation in Lymphoid Cells, Cell, vol.136, issue.2, pp.337-351, 2009.
DOI : 10.1016/j.cell.2008.11.051

O. Ksionda, A. Saveliev, R. Köchl, J. Rapley, M. Faroudi et al., Mechanism and function of Vav1 localisation in TCR signalling, Journal of Cell Science, vol.125, issue.22, pp.5302-5314, 2012.
DOI : 10.1242/jcs.105148

N. Bisson, D. A. James, G. Ivosev, S. A. Tate, R. Bonner et al., Selected reaction monitoring mass spectrometry reveals the dynamics of signaling through the GRB2 adaptor, Nature Biotechnology, vol.16, issue.7, pp.653-658, 2011.
DOI : 10.1038/nprot.2009.57

K. Neumann, T. Oellerich, H. Urlaub, and J. Wienands, The B-lymphoid Grb2 interaction code, Immunological Reviews, vol.161, issue.1, pp.135-149, 2009.
DOI : 10.4049/jimmunol.171.8.4227

M. Naramura, H. K. Kole, R. Hu, and H. Gu, Altered thymic positive selection and intracellular signals in Cbl-deficient mice, Proceedings of the National Academy of Sciences, vol.394, issue.6692, pp.15547-15552, 1998.
DOI : 10.1038/28771

E. Naik, J. D. Webster, J. Devoss, J. Liu, R. Suriben et al., Regulation of proximal T cell receptor signaling and tolerance induction by deubiquitinase Usp9X, The Journal of Experimental Medicine, vol.211, issue.10
DOI : 10.1016/S1074-7613(00)80032-1

S. S. Kholmanskikh, H. B. Koeller, A. Wynshaw-boris, T. Gomez, P. C. Letourneau et al., Calcium-dependent interaction of Lis1 with IQGAP1 and Cdc42 promotes neuronal motility, Nature Neuroscience, vol.166, issue.1, pp.50-57, 2005.
DOI : 10.1083/jcb.200402082

C. Pedros, G. Gaud, I. Bernard, S. Kassem, M. Chabod et al., Modulates Regulatory T Cell Function and Inflammatory Bowel Disease Development, The Journal of Immunology, vol.195, issue.4, pp.1608-1616, 2015.
DOI : 10.4049/jimmunol.1402562

S. Hwang, K. Song, R. Lesourne, J. Lee, J. Pinkhasov et al., Reduced TCR signaling potential impairs negative selection but does not result in autoimmune disease, The Journal of Experimental Medicine, vol.2, issue.10, pp.1781-1795, 2012.
DOI : 10.1038/ni1455

B. Schwanhäusser, D. Busse, N. Li, G. Dittmar, J. Schuchhardt et al., Global quantification of mammalian gene expression control, Nature, vol.323, issue.7347, pp.337-342, 2011.
DOI : 10.1016/S0022-2836(02)00994-4

. Acknowledgments, K. We, J. Hogquist, ?. Chiang-for-providing-the-nur77-gfp-transgenic-mice, G. G. /-?-mice et al., facility and the INSERM UMS006-CREFRE animal care facility; A. Saoudi for critical reading of the manuscript; and A. Mitra for the statistical analysis Funding: This work was supported by National Institute of Child Health and Human Development; the Fondation pour la Recherche sur la Sclérose en Plaque (ARSEP); a Marie Curie International Reintegration Grant (R.L.); the French Ministry of Higher Education and Research (PhD fellowships for AA.); the Région Midi-Pyrénées; the Fonds Européens de Développement Régional, FEDER; the Toulouse métropole; and the French Ministry of Research with the Investissement d'Avenir Infrastructures Nationales en Biologie et Santé program (ProFI, Proteomics French Infrastructure project, ANR-10-INBS-08) Author contributions: E.Z. and J.L. performed flow cytometric analysisF. performed experiments for MS; L.L. performed RT-PCR analysis; G.B. performed flow cytometric analysis of T cells in Bim ?/? Themis1 ?/? mice; J.A. performed experiments for revision of the manuscript; M.M and A.G.d.P. performed analysis of MS data, A.G.d.P. and O.B.-S. supervised MS experiments; P.E.L. and R.L

E. Zvezdova, J. Mikolajczak, A. Garreau, M. Marcellin, L. Rigal et al., Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability, Final Publication 17 Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability, p.51, 1126.
DOI : 10.1038/nature10098

O. Acuto, D. Bartolo, V. , M. , and F. , Tailoring T-cell receptor signals by proximal negative feedback mechanisms, Nature Reviews Immunology, vol.19, issue.9, pp.699-712, 2008.
DOI : 10.3934/dcdsb.2003.3.343

URL : https://hal.archives-ouvertes.fr/pasteur-00369557

D. Aki, W. Zhang, and Y. C. Liu, The E3 ligase Itch in immune regulation and beyond, Immunological Reviews, vol.13, issue.1, pp.6-26, 2015.
DOI : 10.1038/nri3447

S. M. Alam and N. R. Gascoigne, Posttranslational regulation of TCR Valpha allelic exclusion during T cell differentiation, J Immunol, vol.160, pp.3883-3890, 1998.

B. Alarcon, B. Berkhout, J. Breitmeyer, and C. Terhorst, Assembly of the human T cell receptor-CD3 complex takes place in the endoplasmic reticulum and involves intermediary complexes between the CD3-gamma.delta.epsilon core and single T cell receptor alpha or beta chains, J Biol Chem, vol.263, pp.2953-2961, 1988.

A. Alcover and B. And-alarcón, Internalization and Intracellular Fate of TCR-CD3 Complexes, Critical Reviews??? in Immunology, vol.20, issue.4, pp.325-346, 2000.
DOI : 10.1615/CritRevImmunol.v20.i4.20

URL : https://hal.archives-ouvertes.fr/hal-00137563

A. Y. Amerik and M. Hochstrasser, Mechanism and function of deubiquitinating enzymes, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, vol.1695, issue.1-3, 2004.
DOI : 10.1016/j.bbamcr.2004.10.003

M. S. Anderson and M. A. Su, AIRE expands: new roles in immune tolerance and beyond, Nature Reviews Immunology, vol.3, issue.4, pp.247-258, 2016.
DOI : 10.1053/j.gastro.2006.09.008

M. W. Appleby, J. A. Gross, M. P. Cooke, S. D. Levin, X. Qian et al., Defective T cell receptor signaling in mice lacking the thymic isoform of p59fyn, Cell, vol.70, issue.5, pp.751-763, 1992.
DOI : 10.1016/0092-8674(92)90309-Z

C. Ardavin, L. Wu, C. L. Li, and K. Shortman, Thymic dendritic cells and T cells develop simultaneously in the thymus from a common precursor population, Nature, vol.362, issue.6422, pp.761-763, 1993.
DOI : 10.1038/362761a0

P. G. Ashton-rickardt, L. Van-kaer, T. N. Schumacher, H. L. Ploegh, and S. Tonegawa, Peptide contributes to the specificity of positive selection of CD8+ T cells in the thymus, Cell, vol.73, issue.5, pp.1041-1049, 1993.
DOI : 10.1016/0092-8674(93)90281-T

R. G. Baker, C. J. Hsu, D. Lee, M. S. Jordan, J. S. Maltzman et al., The Adapter Protein SLP-76 Mediates "Outside-In" Integrin Signaling and Function in T Cells, Molecular and Cellular Biology, vol.29, issue.20, pp.5578-5589, 2009.
DOI : 10.1128/MCB.00283-09

L. Balagopalan, N. P. Coussens, E. Sherman, L. E. Samelson, and C. L. Sommers, The LAT Story: A Tale of Cooperativity, Coordination, and Choreography, Cold Spring Harbor Perspectives in Biology, vol.2, issue.8, p.5512, 2010.
DOI : 10.1101/cshperspect.a005512

C. Behrends and J. W. Harper, Constructing and decoding unconventional ubiquitin chains, Nature Structural & Molecular Biology, vol.18, issue.5, 2011.
DOI : 10.1038/jid.2010.259

M. J. Bevan, In a radiation chimaera, host H???2 antigens determine immune responsiveness of donor cytotoxic cells, Nature, vol.1, issue.5627, pp.417-418, 1977.
DOI : 10.1084/jem.142.6.1349

N. R. Bhakta, D. Y. Oh, L. , and R. S. , Calcium oscillations regulate thymocyte motility during positive selection in the three-dimensional thymic environment, Nature Immunology, vol.260, issue.2, pp.143-151, 2005.
DOI : 10.1038/35006664

P. Bhowmick, R. Pancsa, M. Guharoy, and P. Tompa, Functional Diversity and Structural Disorder in the Human Ubiquitination Pathway, PLoS ONE, vol.14, issue.5, p.65443, 2013.
DOI : 10.1371/journal.pone.0065443.s013

D. D. Billadeau, T Cell Activation at the Immunological Synapse: Vesicles Emerge for LATer Signaling, Science Signaling, vol.3, issue.121, p.16, 2010.
DOI : 10.1126/scisignal.3121pe16

C. Brockmeyer, W. Paster, D. Pepper, C. P. Tan, D. C. Trudgian et al., T Cell Receptor (TCR)-induced Tyrosine Phosphorylation Dynamics Identifies THEMIS as a New TCR Signalosome Component, Journal of Biological Chemistry, vol.83, issue.9, pp.7535-7547, 2011.
DOI : 10.1006/cimm.2001.1827

E. Brugnera, A. Bhandoola, R. Cibotti, Q. Yu, T. I. Guinter et al., Coreceptor Reversal in the Thymus, Immunity, vol.13, issue.1, pp.59-71, 2000.
DOI : 10.1016/S1074-7613(00)00008-X

N. Bédard, S. Jammoul, T. Moore, L. Wykes, P. L. Hallauer et al., Inactivation of the ubiquitin-specific protease 19 deubiquitinating enzyme protects against muscle wasting, The FASEB Journal, vol.29, issue.9, pp.3889-3898, 2015.
DOI : 10.1126/scisignal.2001878

M. E. Call, J. Pyrdol, M. Wiedmann, and K. W. Wucherpfennig, The Organizing Principle in the Formation of the T Cell Receptor-CD3 Complex, Cell, vol.111, issue.7, pp.967-979, 2002.
DOI : 10.1016/S0092-8674(02)01194-7

R. Cao, Y. Tsukada, and Y. Zhang, Role of Bmi-1 and Ring1A in H2A Ubiquitylation and Hox Gene Silencing, Molecular Cell, vol.20, issue.6, pp.845-854, 2005.
DOI : 10.1016/j.molcel.2005.12.002

A. C. Carpenter and R. Bosselut, Decision checkpoints in the thymus, Nature Immunology, vol.20, issue.8, pp.666-673, 2010.
DOI : 10.4049/jimmunol.181.5.2980

J. D. Carter, B. G. Neel, and U. Lorenz, The tyrosine phosphatase SHP-1 influences thymocyte selection by setting TCR signaling thresholds, International Immunology, vol.11, issue.12, 1999.
DOI : 10.1016/S1074-7613(00)80554-3

M. Chabod, C. Pedros, L. Lamouroux, C. Colacios, I. Bernard et al., A Spontaneous Mutation of the Rat Themis Gene Leads to Impaired Function of Regulatory T Cells Linked to Inflammatory Bowel Disease, PLoS Genetics, vol.19, issue.1, 2012.
DOI : 10.1371/journal.pgen.1002461.s005

A. Ciechanover, S. Elias, H. Heller, S. Ferber, and A. Hershko, Characterization of the heatstable polypeptide of the ATP-dependent proteolytic system from reticulocytes, J Biol Chem, vol.255, pp.7525-7528, 1980.

A. Ciechanover, H. Heller, S. Elias, A. L. Haas, and A. Hershko, ATP-dependent conjugation of reticulocyte proteins with the polypeptide required for protein degradation., Proceedings of the National Academy of Sciences, vol.77, issue.3, pp.1365-1368, 1980.
DOI : 10.1073/pnas.77.3.1365

E. S. Coyne and S. S. Wing, The business of deubiquitination ??? location, location, location, F1000Research, 2016.
DOI : 10.12688/f1000research.7220.1

M. A. Daniels, E. Teixeiro, J. Gill, B. Hausmann, D. Roubaty et al., Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling, Nature, vol.362, issue.7120, pp.724-729, 2006.
DOI : 10.1038/362070a0

V. P. Dave, D. Allman, R. Keefe, R. R. Hardy, and D. J. Kappes, HD mice: A novel mouse mutant with a specific defect in the generation of CD4+ T cells, Proceedings of the National Academy of Sciences, vol.6, issue.6, pp.8187-8192, 1998.
DOI : 10.1016/S1074-7613(00)80442-2

J. Dekoning, L. Dimolfetto, C. Reilly, Q. Wei, W. L. Havran et al., Thymic cortical epithelium is sufficient for the development of mature T cells in relB-deficient mice, J Immunol, vol.158, pp.2558-2566, 1997.

P. C. Dubois, G. Trynka, L. Franke, K. A. Hunt, J. Romanos et al., Multiple common variants for celiac disease influencing immune gene expression, Nature Genetics, vol.573, issue.4, pp.295-302, 2010.
DOI : 10.4049/jimmunol.170.8.3986

A. Dufner, A. Kisser, S. Niendorf, A. Basters, S. Reissig et al., The ubiquitin-specific protease USP8 is critical for the development and homeostasis of T cells, Nature Immunology, vol.12, issue.9, pp.950-960, 2015.
DOI : 10.1016/0306-9877(95)90228-7

I. L. Dzhagalov, K. G. Chen, P. Herzmark, and E. A. Robey, Elimination of Self-Reactive T Cells in the Thymus: A Timeline for Negative Selection, PLoS Biology, vol.12, issue.5, 2013.
DOI : 10.1371/journal.pbio.1001566.s007

F. Finetti, A. Onnis, and C. T. Baldari, Regulation of Vesicular Traffic at the T Cell Immune Synapse: Lessons from the Primary Cilium, Traffic, vol.23, issue.3, pp.241-249, 2015.
DOI : 10.1016/j.cub.2013.04.019

G. Fu, J. Casas, S. Rigaud, V. Rybakin, F. Lambolez et al., Themis sets the signal threshold for positive and negative selection in T-cell development, Nature, vol.167, issue.7480, pp.441-445, 2013.
DOI : 10.1084/jem.20092170

G. Fu, S. Vallee, V. Rybakin, M. V. Mcguire, J. Ampudia et al., Themis controls thymocyte selection through regulation of T cell antigen receptor???mediated signaling, Nature Immunology, vol.15, issue.8, pp.848-856, 2009.
DOI : 10.4049/jimmunol.167.9.4966

G. Fu, S. Vallée, V. Rybakin, M. V. Mcguire, J. Ampudia et al., Themis controls thymocyte selection through regulation of T cell antigen receptor???mediated signaling, Nature Immunology, vol.15, issue.8, pp.848-856, 2009.
DOI : 10.4049/jimmunol.167.9.4966

A. M. Gallegos and M. J. Bevan, Central Tolerance to Tissue-specific Antigens Mediated by Direct and Indirect Antigen Presentation, The Journal of Experimental Medicine, vol.152, issue.8, pp.1039-1049, 2004.
DOI : 10.1038/ni854

E. K. Gao, D. Lo, R. Cheney, O. Kanagawa, and J. Sprent, Abnormal differentiation of thymocytes in mice treated with cyclosporin A, Nature, vol.336, issue.6195, pp.176-179, 1988.
DOI : 10.1038/336176a0

J. X. Gao, H. Zhang, X. F. Bai, J. Wen, X. Zheng et al., Perinatal Blockade of B7-1 and B7-2 Inhibits Clonal Deletion of Highly Pathogenic Autoreactive T Cells, The Journal of Experimental Medicine, vol.6, issue.8, pp.959-971, 2002.
DOI : 10.1038/71540

K. C. Garcia, M. Degano, R. L. Stanfield, A. Brunmark, M. R. Jackson et al., An alpha beta T Cell Receptor Structure at 2.5 A and Its Orientation in the TCR-MHC Complex, Science, vol.274, issue.5285, pp.209-219, 1996.
DOI : 10.1126/science.274.5285.209

D. I. Godfrey, J. Kennedy, T. Suda, and A. Zlotnik, A developmental pathway involving four phenotypically and functionally distinct subsets of CD3-CD4-CD8-triple-negative adult mouse thymocytes defined by CD44 and CD25 expression, J Immunol, vol.150, pp.4244-4252, 1993.

C. Grabbe and I. Dikic, Functional Roles of Ubiquitin-Like Domain (ULD) and Ubiquitin-Binding Domain (UBD) Containing Proteins, Chemical Reviews, vol.109, issue.4, pp.1481-1494, 2009.
DOI : 10.1021/cr800413p

U. Grawunder and E. Harfst, How to make ends meet in V(D)J recombination, Current Opinion in Immunology, vol.13, issue.2, pp.186-194, 2001.
DOI : 10.1016/S0952-7915(00)00203-X

M. Groettrup, C. Pelzer, G. Schmidtke, and K. Hofmann, Activating the ubiquitin family: UBA6 challenges the field, Trends in Biochemical Sciences, vol.33, issue.5, pp.230-237, 2008.
DOI : 10.1016/j.tibs.2008.01.005

T. Groves, P. Katis, Z. Madden, K. Manickam, D. Ramsden et al., In vitro maturation of clonal CD4+CD8+ cell lines in response to TCR engagement, J Immunol, vol.154, pp.5011-5022, 1995.

T. Groves, P. Smiley, M. P. Cooke, K. Forbush, R. M. Perlmutter et al., Fyn Can Partially Substitute for Lck in T Lymphocyte Development, Immunity, vol.5, issue.5, pp.417-428, 1996.
DOI : 10.1016/S1074-7613(00)80498-7

D. Guo, Q. Teng, J. , and C. , NOTCH and phosphatidylinositide 3-kinase/phosphatase and tensin homolog deleted on chromosome ten/AKT/mammalian target of rapamycin (mTOR) signaling in T-cell development and T-cell acute lymphoblastic leukemia, Leukemia & Lymphoma, vol.24, issue.18, pp.1200-1210, 2011.
DOI : 10.3324/haematol.2009.011999

A. L. Haas, J. V. Warms, A. Hershko, R. , and I. A. , Ubiquitin-activating enzyme. Mechanism and role in protein-ubiquitin conjugation, J Biol Chem, vol.257, pp.2543-2548, 1982.

K. Haglund, S. Sigismund, S. Polo, I. Szymkiewicz, D. Fiore et al., Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation, Nature Cell Biology, vol.18, issue.5, pp.461-466, 2003.
DOI : 10.1093/nar/18.12.3587

G. Hernández-hoyos, S. J. Sohn, E. V. Rothenberg, A. , and J. , Lck Activity Controls CD4/CD8 T Cell Lineage Commitment, Immunity, vol.12, issue.3, pp.313-322, 2000.
DOI : 10.1016/S1074-7613(00)80184-3

A. Hershko, A. Ciechanover, H. Heller, A. L. Haas, R. et al., Proposed role of ATP in protein breakdown: conjugation of protein with multiple chains of the polypeptide of ATP-dependent proteolysis., Proceedings of the National Academy of Sciences, vol.77, issue.4, pp.1783-1786, 1980.
DOI : 10.1073/pnas.77.4.1783

A. Hershko, A. Ciechanover, R. , and I. A. , Resolution of the ATP-dependent proteolytic system from reticulocytes: a component that interacts with ATP., Proceedings of the National Academy of Sciences, vol.76, issue.7, pp.3107-3110, 1979.
DOI : 10.1073/pnas.76.7.3107

T. Hettmann and J. M. And-leiden, NF-??B Is Required for the Positive Selection of CD8+ Thymocytes, The Journal of Immunology, vol.165, issue.9, pp.5004-5010, 2000.
DOI : 10.4049/jimmunol.165.9.5004

K. A. Hogquist, J. , and S. C. , The self-obsession of T cells: how TCR signaling thresholds affect fate 'decisions' and effector function, Nature Immunology, vol.340, issue.9, pp.815-823, 2014.
DOI : 10.1084/jem.20122528

K. A. Hogquist, S. C. Jameson, W. R. Heath, J. L. Howard, M. J. Bevan et al., T cell receptor antagonist peptides induce positive selection, Cell, vol.76, issue.1, pp.17-27, 1994.
DOI : 10.1016/0092-8674(94)90169-4

J. C. Houtman, H. Yamaguchi, M. Barda-saad, A. Braiman, B. Bowden et al., Oligomerization of signaling complexes by the multipoint binding of GRB2 to both LAT and SOS1, Nature Structural & Molecular Biology, vol.2003, issue.9, pp.798-805, 2006.
DOI : 10.1016/j.bpc.2004.12.015

H. Hu, H. Wang, Y. Xiao, J. Jin, J. H. Chang et al., Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination, The Journal of Experimental Medicine, vol.2, issue.3, pp.399-414, 2016.
DOI : 10.1146/annurev-immunol-030409-101212

H. Huang, M. S. Jeon, L. Liao, C. Yang, C. Elly et al., K33-Linked Polyubiquitination of T Cell Receptor-?? Regulates Proteolysis-Independent T Cell Signaling, Immunity, vol.33, issue.1, pp.60-70, 2010.
DOI : 10.1016/j.immuni.2010.07.002

K. Husnjak and I. Dikic, Ubiquitin-Binding Proteins: Decoders of Ubiquitin-Mediated Cellular Functions, Annual Review of Biochemistry, vol.81, issue.1, pp.291-322, 2012.
DOI : 10.1146/annurev-biochem-051810-094654

A. Iphöfer, A. Kummer, M. Nimtz, A. Ritter, T. Arnold et al., Profiling Ubiquitin Linkage Specificities of Deubiquitinating Enzymes with Branched Ubiquitin Isopeptide Probes, ChemBioChem, vol.44, issue.10, pp.1416-1420, 2012.
DOI : 10.1016/j.molcel.2011.06.034

J. Izrailit, A. Jaiswal, W. Zheng, M. F. Moran, and M. Reedijk, Cellular stress induces TRB3/USP9x-dependent Notch activation in cancer, Oncogene, vol.7, issue.8, 2016.
DOI : 10.1074/mcp.M114.038596

A. S. Jahan, M. Lestra, L. K. Swee, Y. Fan, M. M. Lamers et al., Usp12 stabilizes the T-cell receptor complex at the cell surface during signaling, Proceedings of the National Academy of Sciences, vol.113, issue.6, pp.705-714, 2016.
DOI : 10.1126/science.1231143

I. K. Jang, J. Zhang, Y. J. Chiang, H. K. Kole, D. G. Cronshaw et al., Grb2 functions at the top of the T-cell antigen receptor-induced tyrosine kinase cascade to control thymic selection, Proceedings of the National Academy of Sciences, vol.29, issue.3, 2010.
DOI : 10.1038/ng750

M. K. Jenkins, R. H. Schwartz, and D. M. Pardoll, Effects of cyclosporine A on T cell development and clonal deletion, Science, vol.241, issue.4873, pp.1655-1658, 1988.
DOI : 10.1126/science.3262237

K. D. Jensen, X. Su, S. Shin, L. Li, S. Youssef et al., Thymic Selection Determines ???? T Cell Effector Fate: Antigen-Naive Cells Make Interleukin-17 and Antigen-Experienced Cells Make Interferon ??, Immunity, vol.29, issue.1, pp.90-100, 2008.
DOI : 10.1016/j.immuni.2008.04.022

URL : https://doi.org/10.1016/j.immuni.2008.04.022

S. Jin, S. Tian, Y. Chen, C. Zhang, W. Xie et al., USP19 modulates autophagy and antiviral immune responses by deubiquitinating Beclin???1, The EMBO Journal, vol.35, issue.8, pp.866-880, 2016.
DOI : 10.15252/embj.201593596

URL : http://embojnl.embopress.org/content/embojnl/35/8/866.full.pdf

A. L. Johnson, L. Aravind, N. Shulzhenko, A. Morgun, S. Y. Choi et al., Themis is a member of a new metazoan gene family and is required for the completion of thymocyte positive selection, Nature Immunology, vol.34, issue.8, pp.831-839, 2009.
DOI : 10.4049/jimmunol.167.4.2030

D. J. Johnson, L. I. Pao, S. Dhanji, K. Murakami, P. S. Ohashi et al., Shp1 regulates T cell homeostasis by limiting IL-4 signals, The Journal of Experimental Medicine, vol.163, issue.7, pp.1419-1431, 2013.
DOI : 10.1385/IR:28:1:25

M. M. Juntilla, J. A. Wofford, M. J. Birnbaum, J. C. Rathmell, and G. A. Koretzky, Akt1 and Akt2 are required for ??beta thymocyte survival and differentiation, Proceedings of the National Academy of Sciences, vol.178, issue.9, pp.12105-12110, 2007.
DOI : 10.4049/jimmunol.178.9.5443

Y. Kee, N. Lyon, and J. M. Huibregtse, The Rsp5 ubiquitin ligase is coupled to and antagonized by the Ubp2 deubiquitinating enzyme, The EMBO Journal, vol.16, issue.13, pp.2414-2424, 2005.
DOI : 10.1128/MCB.16.7.3255

K. W. Kim, R. A. Myers, J. H. Lee, C. Igartua, K. E. Lee et al., Genome-wide association study of recalcitrant atopic dermatitis in Korean children, Journal of Allergy and Clinical Immunology, vol.136, issue.3, pp.678-684, 2015.
DOI : 10.1016/j.jaci.2015.03.030

H. Kishimoto and J. Sprent, Several Different Cell Surface Molecules Control Negative Selection of Medullary Thymocytes, The Journal of Experimental Medicine, vol.152, issue.1, pp.65-73, 1999.
DOI : 10.1007/BF02786320

P. Kisielow, H. Blüthmann, U. D. Staerz, M. Steinmetz, V. Boehmer et al., Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes, Nature, vol.333, issue.6175, pp.742-746, 1988.
DOI : 10.1038/333742a0

D. Komander, M. J. Clague, and S. Urbé, Breaking the chains: structure and function of the deubiquitinases, Nature Reviews Molecular Cell Biology, vol.280, issue.8, pp.550-563, 2009.
DOI : 10.1091/mbc.11.10.3365

D. Komander and M. And-rape, The Ubiquitin Code, Annual Review of Biochemistry, vol.81, issue.1, pp.203-229, 2012.
DOI : 10.1146/annurev-biochem-060310-170328

D. Komander, F. Reyes-turcu, J. D. Licchesi, P. Odenwaelder, K. D. Wilkinson et al., Molecular discrimination of structurally equivalent Lys 63-linked and linear polyubiquitin chains, EMBO reports, vol.10, issue.5, pp.466-473, 2009.
DOI : 10.1038/sj.onc.1211042

A. Kosugi, J. Sakakura, K. Yasuda, M. Ogata, and T. Hamaoka, Involvement of SHP-1 Tyrosine Phosphatase in TCR-Mediated Signaling Pathways in Lipid Rafts, Immunity, vol.14, issue.6, pp.669-680, 2001.
DOI : 10.1016/S1074-7613(01)00146-7

M. Kronenberg and I. Engel, On the road: progress in finding the unique pathway of invariant NKT cell differentiation, Current Opinion in Immunology, vol.19, issue.2, pp.186-193, 2007.
DOI : 10.1016/j.coi.2007.02.009

L. L. Lanier, H. Spits, and J. H. Phillips, The developmental relationship between NK cells and T cells, Immunology Today, vol.13, issue.10, pp.392-395, 1992.
DOI : 10.1016/0167-5699(92)90087-N

P. Larghi, D. J. Williamson, J. M. Carpier, S. Dogniaux, K. Chemin et al., VAMP7 controls T cell activation by regulating the recruitment and phosphorylation of vesicular Lat at TCR-activation sites, Nature Immunology, vol.172, issue.7, pp.723-731, 2013.
DOI : 10.4049/jimmunol.172.1.292

J. G. Lee, W. Kim, S. Gygi, Y. , and Y. , Characterization of the Deubiquitinating Activity of USP19 and Its Role in Endoplasmic Reticulum-associated Degradation, Journal of Biological Chemistry, vol.289, issue.6, pp.3510-3517, 2014.
DOI : 10.1016/S0092-8674(00)00167-7

K. Lee, K. T. Nam, S. H. Cho, P. Gudapati, Y. Hwang et al., Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia, The Journal of Experimental Medicine, vol.95, issue.4, pp.713-728, 2012.
DOI : 10.1073/pnas.1016132108

G. Legname, B. Seddon, M. Lovatt, P. Tomlinson, N. Sarner et al., Inducible Expression of a p56Lck Transgene Reveals a Central Role for Lck in the Differentiation of CD4 SP Thymocytes, Immunity, vol.12, issue.5, pp.537-546, 2000.
DOI : 10.1016/S1074-7613(00)80205-8

R. Lesourne, S. Uehara, J. Lee, K. D. Song, L. Li et al., Themis, a T cell???specific protein important for late thymocyte development, Nature Immunology, vol.5, issue.8, pp.840-847, 2009.
DOI : 10.1016/S1525-1578(10)60455-2

R. Lesourne, E. Zvezdova, K. D. Song, D. El-khoury, S. Uehara et al., Interchangeability of Themis1 and Themis2 in Thymocyte Development Reveals Two Related Proteins with Conserved Molecular Function, The Journal of Immunology, vol.189, issue.3, pp.1154-1161, 2012.
DOI : 10.4049/jimmunol.1200123

H. Lin, L. Yin, J. Reid, K. D. Wilkinson, and S. S. Wing, Divergent N-terminal Sequences of a Deubiquitinating Enzyme Modulate Substrate Specificity, Journal of Biological Chemistry, vol.260, issue.23, pp.20357-20363, 2001.
DOI : 10.1021/bi0007019

J. T. Lin, N. B. Lineberry, M. G. Kattah, L. L. Su, P. J. Utz et al., Naive CD4 T Cell Proliferation Is Controlled by Mammalian Target of Rapamycin Regulation of GRAIL Expression, The Journal of Immunology, vol.182, issue.10, pp.5919-5928, 2009.
DOI : 10.4049/jimmunol.0803986

S. K. Liu, N. Fang, G. A. Koretzky, and C. J. Mcglade, The hematopoietic-specific adaptor protein Gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors, Current Biology, vol.9, issue.2, pp.67-75, 1999.
DOI : 10.1016/S0960-9822(99)80017-7

X. Liu and R. Bosselut, Duration of TCR signaling controls CD4-CD8 lineage differentiation in vivo, Nature Immunology, vol.344, issue.3, pp.280-288, 2004.
DOI : 10.1038/344742a0

Y. C. Liu, Ubiquitin Ligases and the Immune Response, Annual Review of Immunology, vol.22, issue.1, pp.81-127, 2004.
DOI : 10.1146/annurev.immunol.22.012703.104813

N. Lopes, A. Sergé, P. Ferrier, and M. Irla, Thymic Crosstalk Coordinates Medulla Organization and T-Cell Tolerance Induction, Frontiers in Immunology, vol.180, issue.9, p.365, 2015.
DOI : 10.4049/jimmunol.180.8.5384

URL : https://hal.archives-ouvertes.fr/hal-01201019

U. Lorenz, SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels, Immunological Reviews, vol.57, issue.1, pp.342-359, 2009.
DOI : 10.4049/jimmunol.169.9.4712

B. Malissen, C. Gregoire, M. Malissen, R. , and R. , Integrative biology of T cell activation, Nature Immunology, vol.256, issue.9, pp.790-797, 2014.
DOI : 10.1016/j.immuni.2009.03.010

B. A. Malynn and A. Ma, Ubiquitin Makes Its Mark on Immune Regulation, Immunity, vol.33, issue.6, pp.843-852, 2010.
DOI : 10.1016/j.immuni.2010.12.007

S. Mariathasan, A. Zakarian, D. Bouchard, A. M. Michie, J. C. Zúñiga-pflücker et al., Duration and Strength of Extracellular Signal-Regulated Kinase Signals Are Altered During Positive Versus Negative Thymocyte Selection, The Journal of Immunology, vol.167, issue.9, pp.4966-4973, 2001.
DOI : 10.4049/jimmunol.167.9.4966

F. Mattiroli and T. K. Sixma, Lysine-targeting specificity in ubiquitin and ubiquitin-like modification pathways, Nature Structural & Molecular Biology, vol.265, issue.4, pp.308-316, 2014.
DOI : 10.1016/j.tibs.2008.09.004

P. Matzinger, R. Zamoyska, and H. Waldmann, Self tolerance is H???2-restricted, Nature, vol.158, issue.5961, pp.738-741, 1984.
DOI : 10.1038/308738a0

L. K. Mcneil, T. K. Starr, and K. A. Hogquist, A requirement for sustained ERK signaling during thymocyte positive selection in vivo, Proceedings of the National Academy of Sciences, vol.438, issue.1-2, pp.13574-13579, 2005.
DOI : 10.1016/S0014-5793(98)01268-X

Y. Mei, A. A. Hahn, S. Hu, Y. , and X. , The USP19 Deubiquitinase Regulates the Stability of c-IAP1 and c-IAP2, Journal of Biological Chemistry, vol.65, issue.41, pp.35380-35387, 2011.
DOI : 10.1126/science.281.5383.1680

H. J. Melichar, J. O. Ross, P. Herzmark, K. A. Hogquist, and E. A. Robey, Distinct Temporal Patterns of T Cell Receptor Signaling During Positive Versus Negative Selection in Situ, Science Signaling, vol.12, issue.2, p.92, 2013.
DOI : 10.1006/cimm.2001.1895

M. B. Metzger, J. N. Pruneda, R. E. Klevit, and A. M. Weissman, RING-type E3 ligases: Master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, vol.1843, issue.1, pp.47-60, 2014.
DOI : 10.1016/j.bbamcr.2013.05.026

C. Michelle, P. Vourc-'h, L. Mignon, A. , and C. R. , What Was the Set of Ubiquitin and Ubiquitin-Like Conjugating Enzymes in the Eukaryote Common Ancestor?, Journal of Molecular Evolution, vol.101, issue.5834, pp.616-628, 2009.
DOI : 10.1093/oxfordjournals.molbev.a003980

T. J. Molina, K. Kishihara, D. P. Siderovski, W. Van-ewijk, A. Narendran et al., Profound block in thymocyte development in mice lacking p56lck, Nature, vol.357, issue.6374, pp.161-164, 1992.
DOI : 10.1038/357161a0

S. Murata, Y. Takahama, and K. Tanaka, Thymoproteasome: probable role in generating positively selecting peptides, Current Opinion in Immunology, vol.20, issue.2, pp.192-196, 2008.
DOI : 10.1016/j.coi.2008.03.002

M. A. Murphy, R. G. Schnall, D. J. Venter, L. Barnett, I. Bertoncello et al., Tissue Hyperplasia and Enhanced T-Cell Signalling via ZAP-70 in c-Cbl-Deficient Mice, Molecular and Cellular Biology, vol.18, issue.8, pp.4872-4882, 1998.
DOI : 10.1128/MCB.18.8.4872

E. Naik and V. M. Dixit, Usp9X Is Required for Lymphocyte Activation and Homeostasis through Its Control of ZAP70 Ubiquitination and PKC?? Kinase Activity, The Journal of Immunology, vol.281, issue.3, pp.3438-3451, 2016.
DOI : 10.1074/jbc.M510251200

E. Naik, J. D. Webster, J. Devoss, J. Liu, R. Suriben et al., Regulation of proximal T cell receptor signaling and tolerance induction by deubiquitinase Usp9X, The Journal of Experimental Medicine, vol.211, issue.10, pp.1947-1955, 2014.
DOI : 10.1016/S1074-7613(00)80032-1

T. Nakagawa, W. Roth, P. Wong, A. Nelson, A. Farr et al., Cathepsin L: Critical Role in Ii Degradation and CD4 T Cell Selection in the Thymus, Science, vol.280, issue.5362, pp.450-453, 1998.
DOI : 10.1126/science.280.5362.450

N. Nakamura, K. Harada, M. Kato, and S. Hirose, Ubiquitin-specific protease 19 regulates the stability of the E3 ubiquitin ligase MARCH6, Experimental Cell Research, vol.328, issue.1, pp.207-216, 2014.
DOI : 10.1016/j.yexcr.2014.07.025

M. Naramura, H. K. Kole, R. J. Hu, and H. Gu, Altered thymic positive selection and intracellular signals in Cbl-deficient mice, Proceedings of the National Academy of Sciences, vol.394, issue.6692, pp.15547-15552, 1998.
DOI : 10.1038/28771

I. Negishi, N. Motoyama, K. Nakayama, S. Senju, S. Hatakeyama et al., Essential role for ZAP-70 in both positive and negative selection of thymocytes, Nature, vol.376, issue.6539, pp.435-438, 1995.
DOI : 10.1038/376435a0

J. R. Neilson, M. M. Winslow, E. M. Hur, and G. R. Crabtree, Calcineurin B1 Is Essential for Positive but Not Negative Selection during Thymocyte Development, Immunity, vol.20, issue.3, pp.255-266, 2004.
DOI : 10.1016/S1074-7613(04)00052-4

S. M. Nijman, M. P. Luna-vargas, A. Velds, T. R. Brummelkamp, A. M. Dirac et al., A Genomic and Functional Inventory of Deubiquitinating Enzymes, Cell, vol.123, issue.5, pp.773-786, 2005.
DOI : 10.1016/j.cell.2005.11.007

J. Nikolich-zugich, M. K. Slifka, and I. Messaoudi, The many important facets of T-cell repertoire diversity, Nature Reviews Immunology, vol.14, issue.2, pp.123-132, 2004.
DOI : 10.1016/S1074-7613(01)00086-3

O. Leary, C. E. Lewis, E. L. Oliver, and P. M. , Ubiquitylation as a Rheostat for TCR Signaling: From Targeted Approaches Toward Global Profiling, Front Immunol, vol.6, p.618, 2015.

M. Oh-hora, Calcium signaling in the development and function of T-lineage cells, Immunological Reviews, vol.178, issue.1, pp.210-224, 2009.
DOI : 10.4049/jimmunol.178.1.280

T. Okada, T. Nitta, K. Kaji, A. Takashima, H. Oda et al., Differential Function of Themis CABIT Domains during T Cell Development, PLoS ONE, vol.32, issue.2, p.89115, 2014.
DOI : 10.1371/journal.pone.0089115.s004

P. Outters, S. Jaeger, N. Zaarour, and P. Ferrier, Long-Range Control of V(D)J Recombination & Allelic Exclusion, Adv Immunol, vol.128, pp.363-413, 2015.
DOI : 10.1016/bs.ai.2015.08.002

E. H. Palacios and A. Weiss, Distinct roles for Syk and ZAP-70 during early thymocyte development, The Journal of Experimental Medicine, vol.12, issue.7, pp.1703-1715, 2007.
DOI : 10.1016/S1074-7613(03)00082-7

Y. Park, H. S. Jin, and Y. C. Liu, Regulation of T cell function by the ubiquitin-specific protease USP9X via modulating the Carma1-Bcl10-Malt1 complex, Proceedings of the National Academy of Sciences, vol.110, issue.23, pp.9433-9438, 2013.
DOI : 10.1073/pnas.0606982104

W. Paster, C. Brockmeyer, G. Fu, P. C. Simister, B. De-wet et al., GRB2-Mediated Recruitment of THEMIS to LAT Is Essential for Thymocyte Development, The Journal of Immunology, vol.190, issue.7, pp.3749-3756, 2013.
DOI : 10.4049/jimmunol.1203389

W. Paster, C. Brockmeyer, G. Fu, P. C. Simister, B. De-wet et al., GRB2-Mediated Recruitment of THEMIS to LAT Is Essential for Thymocyte Development, The Journal of Immunology, vol.190, issue.7, pp.3749-3756, 2013.
DOI : 10.4049/jimmunol.1203389

W. Paster, A. M. Bruger, K. Katsch, C. Grégoire, R. Roncagalli et al., A THEMIS:SHP1 complex promotes T-cell survival, The EMBO Journal, vol.34, issue.3, pp.393-409, 2015.
DOI : 10.15252/embj.201387725

M. S. Patrick, H. Oda, K. Hayakawa, Y. Sato, K. Eshima et al., Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes, Proceedings of the National Academy of Sciences of the United States of America, pp.16345-16350, 2009.
DOI : 10.1128/MCB.00793-09

C. Patterson, A New Gun in Town: The U Box Is a Ubiquitin Ligase Domain, Science Signaling, vol.314, issue.6, p.4, 2002.
DOI : 10.1042/bj3140313

P. E. Paz, S. Wang, H. Clarke, X. Lu, D. Stokoe et al., Mapping the Zap-70 phosphorylation sites on LAT (linker for activation of T cells) required for recruitment and activation of signalling proteins in T cells, Biochemical Journal, vol.356, issue.2, pp.461-471, 2001.
DOI : 10.1042/bj3560461

C. Pelzer, I. Kassner, K. Matentzoglu, R. K. Singh, H. P. Wollscheid et al., UBE1L2, a Novel E1 Enzyme Specific for Ubiquitin, Journal of Biological Chemistry, vol.36, issue.32, pp.23010-23014, 2007.
DOI : 10.1038/sj.emboj.7600205

J. Peng, D. Schwartz, J. E. Elias, C. C. Thoreen, D. Cheng et al., A proteomics approach to understanding protein ubiquitination, Nature Biotechnology, vol.1, issue.8, pp.921-926, 2003.
DOI : 10.1021/pr015509n

C. M. Pickart, Targeting of substrates to the 26S proteasome., The FASEB Journal, vol.11, issue.13, pp.1055-1066, 1997.
DOI : 10.1096/fasebj.11.13.9367341

C. M. Pickart, Mechanisms Underlying Ubiquitination, Annual Review of Biochemistry, vol.70, issue.1, pp.503-533, 2001.
DOI : 10.1146/annurev.biochem.70.1.503

C. M. Pickart, Back to the Future with Ubiquitin, Cell, vol.116, issue.2, pp.181-190, 2004.
DOI : 10.1016/S0092-8674(03)01074-2

L. Pintard, A. Willems, and M. Peter, Cullin-based ubiquitin ligases: Cul3???BTB complexes join the family, The EMBO Journal, vol.91, issue.8, pp.1681-1687, 2004.
DOI : 10.1038/sj.emboj.7600186

K. Poalas, E. M. Hatchi, N. Cordeiro, S. M. Dubois, H. M. Leclair et al., Negative regulation of NF-??B signaling in T lymphocytes by the ubiquitin-specific protease USP34, Cell Communication and Signaling, vol.11, issue.1, 2013.
DOI : 10.1038/ni.2070

I. Rhee and A. Veillette, Protein tyrosine phosphatases in lymphocyte activation and autoimmunity, Nature Immunology, vol.76, issue.5, pp.439-447, 2012.
DOI : 10.1016/j.immuni.2010.08.001

S. G. Rhee and Y. S. Bae, Regulation of Phosphoinositide-specific Phospholipase C Isozymes, Journal of Biological Chemistry, vol.88, issue.24, pp.15045-15048, 1997.
DOI : 10.1007/s003359900151

N. S. Roa, D. Ordoñez-rueda, J. R. Chávez-rios, C. Raman, E. A. García-zepeda et al., The carboxy-terminal region of CD5 is required for c-CBL mediated TCR signaling downmodulation in thymocytes, Biochemical and Biophysical Research Communications, vol.432, issue.1, pp.52-59, 2013.
DOI : 10.1016/j.bbrc.2013.01.086

J. O. Ross, H. J. Melichar, B. B. Au-yeung, P. Herzmark, A. Weiss et al., Distinct phases in the positive selection of CD8+ T cells distinguished by intrathymic migration and T-cell receptor signaling patterns, Proceedings of the National Academy of Sciences, vol.16, issue.12, pp.2550-2558, 2014.
DOI : 10.1038/nn.3447

D. Rotin and S. Kumar, Physiological functions of the HECT family of ubiquitin ligases, Nature Reviews Molecular Cell Biology, vol.136, issue.6, pp.398-409, 2009.
DOI : 10.1038/msb4100159

P. E. Row, I. A. Prior, J. Mccullough, M. J. Clague, and S. Urbé, The Ubiquitin Isopeptidase UBPY Regulates Endosomal Ubiquitin Dynamics and Is Essential for Receptor Down-regulation, Journal of Biological Chemistry, vol.4, issue.18, pp.12618-12624, 2006.
DOI : 10.1016/j.bbrc.2003.08.078

K. Saito, T. Kigawa, S. Koshiba, K. Sato, Y. Matsuo et al., The CAP-Gly Domain of CYLD Associates with the Proline-Rich Sequence in NEMO/IKK??, Structure, vol.12, issue.9, pp.1719-1728, 2004.
DOI : 10.1016/j.str.2004.07.012

L. E. Samelson, J. B. Harford, and R. D. Klausner, Identification of the components of the murine T cell antigen receptor complex, Cell, vol.43, issue.1, pp.223-231, 1985.
DOI : 10.1016/0092-8674(85)90027-3

S. Sawcer, G. Hellenthal, M. Pirinen, C. C. Spencer, N. A. Patsopoulos et al., Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis, Nature, vol.48, issue.7359, pp.214-219, 2011.
DOI : 10.1002/1531-8249(200008)48:2<211::AID-ANA11>3.0.CO;2-R

URL : https://hal.archives-ouvertes.fr/hal-00996686

E. Scharschmidt, E. Wegener, V. Heissmeyer, A. Rao, and D. Krappmann, Degradation of Bcl10 Induced by T-Cell Activation Negatively Regulates NF-??B Signaling, Molecular and Cellular Biology, vol.24, issue.9, pp.3860-3873, 2004.
DOI : 10.1128/MCB.24.9.3860-3873.2004

D. G. Schatz, J. , and Y. , Recombination centres and the orchestration of V(D)J recombination, Nature Reviews Immunology, vol.8, issue.4, pp.251-263, 2011.
DOI : 10.1038/ni1481

M. Scheffner, U. Nuber, and J. M. Huibregtse, Protein ubiquitination involving an E1???E2???E3 enzyme ubiquitin thioester cascade, Nature, vol.373, issue.6509, pp.81-83, 1995.
DOI : 10.1038/373081a0

J. Schulze-luehrmann and S. Ghosh, Antigen-Receptor Signaling to Nuclear Factor ??B, Immunity, vol.25, issue.5, pp.701-715, 2006.
DOI : 10.1016/j.immuni.2006.10.010

W. Seufert and S. Jentsch, In vivo function of the proteasome in the ubiquitin pathway, 1992.

S. Shen, M. Zhu, J. Lau, M. Chuck, and W. Zhang, The Essential Role of LAT in Thymocyte Development during Transition from the Double-Positive to Single-Positive Stage, The Journal of Immunology, vol.182, issue.9, pp.5596-5604, 2009.
DOI : 10.4049/jimmunol.0803170

Y. Shinkai, G. Rathbun, K. P. Lam, E. M. Oltz, V. Stewart et al., RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement, Cell, vol.68, issue.5, pp.855-867, 1992.
DOI : 10.1016/0092-8674(92)90029-C

A. Singer, S. Adoro, and J. H. Park, Lineage fate and intense debate: myths, models and mechanisms of CD4- versus CD8-lineage choice, Nature Reviews Immunology, vol.179, issue.10, pp.788-801, 2008.
DOI : 10.4049/jimmunol.179.7.4405

B. Skaug, X. Jiang, C. , and Z. J. , The role of ubiquitin in NF-kappaB regulatory pathways, 2009.

D. E. Spratt, H. Walden, and G. S. Shaw, RBR E3 ubiquitin ligases: new structures, new insights, new questions, Biochemical Journal, vol.14, issue.3, pp.421-437, 2014.
DOI : 10.1074/jbc.M704465200

URL : http://www.biochemj.org/content/ppbiochemj/458/3/421.full.pdf

M. Stawiecka-mirota, W. Pokrzywa, J. Morvan, T. Zoladek, R. Haguenauer-tsapis et al., Targeting of Sna3p to the Endosomal Pathway Depends on Its Interaction with Rsp5p and Multivesicular Body Sorting on Its Ubiquitylation, Traffic, vol.14, issue.9, pp.1280-1296, 2007.
DOI : 10.1128/MCB.14.12.7876

URL : https://hal.archives-ouvertes.fr/hal-00183638

I. Stefanova, B. Hemmer, M. Vergelli, R. Martin, W. E. Biddison et al., TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways, Nature Immunology, vol.186, issue.3, pp.248-254, 2003.
DOI : 10.1084/jem.186.5.757

P. L. Stein, H. M. Lee, S. Rich, and P. Soriano, pp59fyn mutant mice display differential signaling in thymocytes and peripheral T cells, Cell, vol.70, issue.5, pp.741-750, 1992.
DOI : 10.1016/0092-8674(92)90308-Y

T. L. Stephen, A. Tikhonova, J. M. Riberdy, and T. M. Laufer, The Activation Threshold of CD4+ T Cells Is Defined by TCR/Peptide-MHC Class II Interactions in the Thymic Medulla, The Journal of Immunology, vol.183, issue.9, pp.5554-5562, 2009.
DOI : 10.4049/jimmunol.0901104

T. Sugawara, T. Moriguchi, E. Nishida, and Y. Takahama, Differential Roles of ERK and p38 MAP Kinase Pathways in Positive and Negative Selection of T Lymphocytes, Immunity, vol.9, issue.4, pp.565-574, 1998.
DOI : 10.1016/S1074-7613(00)80639-1

K. N. Swatek and D. Komander, Ubiquitin modifications, Cell Research, vol.15, issue.4, pp.399-422, 2016.
DOI : 10.1074/jbc.M111.288449

URL : http://europepmc.org/articles/pmc4822133?pdf=render

H. Takaba, Y. Morishita, Y. Tomofuji, L. Danks, T. Nitta et al., Fezf2 Orchestrates a Thymic Program of Self-Antigen Expression for Immune Tolerance, Cell, vol.163, issue.4, pp.975-987, 2015.
DOI : 10.1016/j.cell.2015.10.013

K. Takada and Y. Takahama, Positive-Selection-Inducing Self-Peptides Displayed by Cortical Thymic Epithelial Cells, Adv Immunol, vol.125, pp.87-110, 2015.
DOI : 10.1016/bs.ai.2014.09.003

Y. Takahama, Journey through the thymus: stromal guides for T-cell development and selection, Nature Reviews Immunology, vol.168, issue.Suppl. 1, pp.127-135, 2006.
DOI : 10.4049/jimmunol.168.6.2609

T. Taniguchi, S. Tanaka, A. Ishii, M. Watanabe, N. Fujitani et al., A Brain-specific Grb2-associated Regulator of Extracellular Signal-regulated Kinase (Erk)/Mitogen-activated Protein Kinase (MAPK) (GAREM) Subtype, GAREM2, Contributes to Neurite Outgrowth of Neuroblastoma Cells by Regulating Erk Signaling, Journal of Biological Chemistry, vol.42, issue.41, pp.29934-29942, 2013.
DOI : 10.1074/mcp.O113.027342

T. Nguyen, H. Andrejeva, D. Gupta, R. Choudhary, C. Hong et al., Deubiquitylating enzyme USP9x regulates hippo pathway activity by controlling angiomotin protein turnover, Cell Discov, vol.2, 2016.

C. B. Thien and W. Y. Langdon, c-Cbl: A regulator of T cell receptor-mediated signalling, Immunology and Cell Biology, vol.4, issue.5, pp.473-482, 1998.
DOI : 10.1016/S1074-7613(00)80415-X

C. B. Thien and W. Y. Langdon, c-Cbl and Cbl-b ubiquitin ligases: substrate diversity and the negative regulation of signalling responses, Biochemical Journal, vol.391, issue.2, pp.153-166, 2005.
DOI : 10.1042/BJ20050892

D. Théard, F. Labarrade, M. Partisani, J. Milanini, H. Sakagami et al., USP9x-mediated deubiquitination of EFA6 regulates de novo tight junction assembly, The EMBO Journal, vol.273, issue.9, pp.1499-1509, 2010.
DOI : 10.1038/ncb1484

X. Tian, N. S. Isamiddinova, R. J. Peroutka, S. J. Goldenberg, M. R. Mattern et al., Characterization of Selective Ubiquitin and Ubiquitin-Like Protease Inhibitors Using a Fluorescence-Based Multiplex Assay Format, ASSAY and Drug Development Technologies, vol.9, issue.2, pp.165-173, 2011.
DOI : 10.1089/adt.2010.0317

N. D. Udeshi, T. Svinkina, P. Mertins, E. Kuhn, D. R. Mani et al., Refined Preparation and Use of Anti-diglycine Remnant (K-??-GG) Antibody Enables Routine Quantification of 10,000s of Ubiquitination Sites in Single Proteomics Experiments, Molecular & Cellular Proteomics, vol.81, issue.3, pp.825-831, 2013.
DOI : 10.1021/ac9004452

J. Van-loosdregt, V. Fleskens, J. Fu, A. B. Brenkman, C. P. Bekker et al., Stabilization of the Transcription Factor Foxp3 by the Deubiquitinase USP7 Increases Treg-Cell-Suppressive Capacity, Immunity, vol.39, issue.2, pp.259-271, 2013.
DOI : 10.1016/j.immuni.2013.05.018

N. S. Van-oers, B. Lowin-kropf, D. Finlay, K. Connolly, and A. Weiss, ???? T Cell Development Is Abolished in Mice Lacking Both Lck and Fyn Protein Tyrosine Kinases, Immunity, vol.5, issue.5, pp.429-436, 1996.
DOI : 10.1016/S1074-7613(00)80499-9

R. Varadan, M. Assfalg, A. Haririnia, S. Raasi, C. Pickart et al., -linked Di-ubiquitin Chain Provides Clues to Functional Diversity of Polyubiquitin Signaling, Journal of Biological Chemistry, vol.149, issue.8, pp.7055-7063, 2004.
DOI : 10.1016/0263-7855(96)00009-4

A. Veillette, M. A. Bookman, E. M. Horak, and J. B. Bolen, The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck, Cell, vol.55, issue.2, pp.301-308, 1988.
DOI : 10.1016/0092-8674(88)90053-0

R. E. Voll, E. Jimi, R. J. Phillips, D. F. Barber, M. Rincon et al., NF-??B Activation by the Pre-T Cell Receptor Serves as a Selective Survival Signal in T Lymphocyte Development, Immunity, vol.13, issue.5, pp.677-689, 2000.
DOI : 10.1016/S1074-7613(00)00067-4

H. Von-boehmer, I. Aifantis, F. Gounari, O. Azogui, L. Haughn et al., Thymic selection revisited: how essential is it?, Immunological Reviews, vol.17, issue.1, pp.62-78, 2003.
DOI : 10.1126/science.1075958

H. Von-boehmer, H. S. Teh, and P. Kisielow, The thymus selects the useful, neglects the useless and destroys the harmful, Immunology Today, vol.10, issue.2, pp.57-61, 1989.
DOI : 10.1016/0167-5699(89)90307-1

S. Vukmanovi?, A. G. Grandea, S. J. Faas, B. B. Knowles, and M. J. Bevan, Positive selection of T-lymphocytes induced by intrathymic injection of a thymic epithelial cell line, Nature, vol.359, issue.6397, pp.729-732, 1992.
DOI : 10.1038/359729a0

T. L. Walunas, A. I. Sperling, R. Khattri, C. B. Thompson, and J. A. Bluestone, CD28 expression is not essential for positive and negative selection of thymocytes or peripheral T cell tolerance, J Immunol, vol.156, pp.1006-1013, 1996.

H. Wang, B. Wei, G. Bismuth, R. , and C. E. , SLP-76-ADAP adaptor module regulates LFA-1, 2009.
DOI : 10.1073/pnas.0900510106

URL : http://www.pnas.org/content/106/30/12436.full.pdf

H. Y. Wang, Y. Altman, D. Fang, C. Elly, Y. Dai et al., Cbl Promotes Ubiquitination of the T Cell Receptor ?? through an Adaptor Function of Zap-70, Journal of Biological Chemistry, vol.13, issue.28, pp.26004-26011, 2001.
DOI : 10.1146/annurev.immunol.17.1.829

L. Wang, K. F. Wildt, J. Zhu, X. Zhang, L. Feigenbaum et al., Distinct functions for the transcription factors GATA-3 and ThPOK during intrathymic differentiation of CD4+ T cells, Nature Immunology, vol.63, issue.10, pp.1122-1130, 2008.
DOI : 10.1002/eji.1830230326

Y. Watanabe, Y. Sasahara, N. Ramesh, M. J. Massaad, Y. Looi et al., T-cell receptor ligation causes Wiskott-Aldrich syndrome protein degradation and F-actin assembly downregulation, Journal of Allergy and Clinical Immunology, vol.132, issue.3, pp.648-655, 2013.
DOI : 10.1016/j.jaci.2013.03.046

K. D. Wilkinson, Ubiquitin: a Nobel protein, Cell, vol.119, pp.741-745, 2004.

R. W. Wilkinson, G. Anderson, J. J. Owen, and E. J. Jenkinson, Positive selection of thymocytes involves sustained interactions with the thymic microenvironment, J Immunol, vol.155, pp.5234-5240, 1995.

A. Wilson, H. R. Macdonald, R. , and F. , Notch 1???Deficient Common Lymphoid Precursors Adopt a B Cell Fate in the Thymus, The Journal of Experimental Medicine, vol.246, issue.7, pp.1003-1012, 2001.
DOI : 10.1016/0167-5699(95)80179-0

L. Wu, M. Antica, G. R. Johnson, R. Scollay, and K. Shortman, Developmental potential of the earliest precursor cells from the adult mouse thymus, Journal of Experimental Medicine, vol.174, issue.6, pp.1617-1627, 1991.
DOI : 10.1084/jem.174.6.1617

M. Xu, B. Skaug, W. Zeng, C. , and Z. J. , A Ubiquitin Replacement Strategy in Human Cells Reveals Distinct Mechanisms of IKK Activation by TNF?? and IL-1??, Molecular Cell, vol.36, issue.2, pp.302-314, 2009.
DOI : 10.1016/j.molcel.2009.10.002

P. Xu, D. M. Duong, N. T. Seyfried, D. Cheng, Y. Xie et al., Quantitative Proteomics Reveals the Function of Unconventional Ubiquitin Chains in Proteasomal Degradation, Cell, vol.137, issue.1, pp.133-145, 2009.
DOI : 10.1016/j.cell.2009.01.041

L. Xue, L. Chiang, C. Kang, and A. Winoto, The role of the PI3K-AKT kinase pathway in T-cell development beyond the ?? checkpoint, European Journal of Immunology, vol.175, issue.11, pp.3200-3207, 2008.
DOI : 10.4049/jimmunol.175.4.2357

H. Yamaguchi and W. A. Hendrickson, Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylation, Nature, vol.384, issue.6608, pp.484-489, 1996.
DOI : 10.1038/384484a0

B. Yang, D. L. Gay, M. K. Macleod, X. Cao, T. Hala et al., Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells, Nature Immunology, vol.91, issue.12, pp.1356-1363, 2008.
DOI : 10.4049/jimmunol.169.5.2236

Y. Ye and M. And-rape, Building ubiquitin chains: E2 enzymes at work, Nature Reviews Molecular Cell Biology, vol.67, issue.11, pp.755-764, 2009.
DOI : 10.1091/mbc.8.8.1427

Q. Yu, B. Erman, A. Bhandoola, S. O. Sharrow, and A. Singer, T Cells, The Journal of Experimental Medicine, vol.13, issue.4, pp.475-487, 2003.
DOI : 10.1093/intimm/9.6.877

URL : https://hal.archives-ouvertes.fr/inserm-00707307

W. Zhang, C. L. Sommers, D. N. Burshtyn, C. C. Stebbins, J. B. Dejarnette et al., Essential Role of LAT in T Cell Development, Immunity, vol.10, issue.3, pp.323-332, 1999.
DOI : 10.1016/S1074-7613(00)80032-1

E. Zvezdova, J. Lee, D. El-khoury, V. Barr, I. Akpan et al., functional mapping of the conserved protein domains within murine Themis1, Immunology and Cell Biology, vol.177, issue.8, pp.721-728, 2014.
DOI : 10.1084/jem.20050176