Rôles de la stimulation chronique du TCR et de la reprogrammation cellulaire dans les lymphomes T périphériques

Abstract : Peripheral T-cell lymphomas (PTCL) are rare non Hodgkin malignant lymphomas emerging from mature T or NK cells. PTCL are highly heterogeneous and mainly misunderstood. As several evidences pointed the potential role of TCR chronic stimulation in human T-cell lymphomagenesis, we developed a murine model based on chronic TCR stimulation to address this question. In this model, transfer of p53-/- T-cells into T-cell deficient mice (CD3e-/-) triggered PTCL development in 60% of cases with a median survival of 230 days while transfer of wt T-cells in CD3e-/- mice did not lead to PTCL development. These PTCL exhibited an effector-memory phenotype CD62LLo-CD44hi-CD122lo-CD25lo associated with a dramatic downregulation of TCR pathway genes expression consistent with a chronic TCR stimulation highlighting it’s implication in lymphomagenesis. The analysis of these PTCL revealed that a large majority of cases (80%) do not depend anymore on TCR stimulation for their growth and survival and that they acquire innate-like features with expression of inhibitory NKR (NKiR) and activating NK receptors (NKaR) as well as the adaptor proteins DAP12 or FceRIg. Expression of these receptors is associated with the expression of SYK and PLC?2, which are classical key effectors downstream of NKaR. We show that these NKaR are functional and can mediate TCR-independent activation in mPTCL and that this signaling is involved in cell survival/proliferation as in vivo blockade of NKG2D and NKp46 delays PTCL development in PTCL transplantation experiments. In parallel, we studied NKR, Syk and PLCg2 expression in human PTCL and found that some entities express a large range of these receptors as well as Syk and PLCg2, suggesting similar lymphomagenesis mechanisms in some human PTCL
Document type :
Theses
Complete list of metadatas

https://tel.archives-ouvertes.fr/tel-02269173
Contributor : Abes Star <>
Submitted on : Thursday, August 22, 2019 - 2:03:07 PM
Last modification on : Wednesday, November 20, 2019 - 7:56:37 AM

File

TH2018CARRASSYLVAIN.pdf
Version validated by the jury (STAR)

Identifiers

  • HAL Id : tel-02269173, version 1

Collections

Citation

Sylvain Carras. Rôles de la stimulation chronique du TCR et de la reprogrammation cellulaire dans les lymphomes T périphériques. Immunologie. Université de Lyon, 2018. Français. ⟨NNT : 2018LYSE1322⟩. ⟨tel-02269173⟩

Share

Metrics

Record views

121

Files downloads

49