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Influence des interactions avec le Soi sur le devenir des cellules T CD4 naïves en phase effectrice

Abstract : Naïve CD4 T cells (CD4 TN) are generated and educated in the thymus. This education is based on their ability to recognize the Self via the TCR-pMHC (Self peptide-MHCII) interaction with a variable affinity. In the periphery, CD4 TN cells circulate between the secondary lymphoid organs, where they still interact with the Self via frequent and transient contact with antigen presenting cells (APCs). Several studies have shown that these contacts influence homeostasis and function of CD4 TN cells. Based on the expression of the Ly-6C protein, my team has shown that CD4 TN Ly-6C⁻ cells interact more strongly with the Self than their Ly-6C⁺ cells counterparts, and that they receive a stronger "Tonic Signaling". In addition, they showed that TCR-pMHC interactions, increase quantitatively the responsiveness during antigenic stimulation, and the ability to differentiate into peripheral regulatory T cells (pTregs) of CD4 TN Ly-6C⁻ cells.Using an in vitro conversion model of CD4 TN Ly-6C⁺ cells into Ly-6C⁻ cells, our main study has shown that the Tonic Signaling, via the calcium pathway of TCR signaling, influences the phenotype and function of naïve CD4 T cells. Interestingly, we have observed that calcineurin-dependent calcium signaling, is partly responsible for the phenotype acquisition of the most self-reactive CD4 TN cells (Ly-6C⁻). An increase in the intracellular calcium concentration enables both the conversion of CD4 TN Ly-6C⁺ cells into Ly-6C⁻ cell, and increases their sensitivity to pTregs differentiation signals in vitro and in vivo. In addition, using an adoptive transfer model of transgenic TCR CD4⁺ T cells (AND), we reproduced in vivo our conversion model. The transfer of these cells into a wildtype mouse increases their potential to interact with APCs by decreasing competition for the pMHC complex. Thus we observe a phenotype and functional conversion of AND cells similar to those observed during our in vitro cultures.In a second study, we have compared CD4 TN Ly-6C⁻ cells to CD4 TN CD5Hi cells. CD5 is another marker reflecting self-reactivity and its expression is correlated with the strength of the TCR signal received. We have observed, despite some phenotypic and functional differences, that these populations of CD4 TN Ly-6C⁻ or CD5Hi are more sensitive to pTegs polarization signals than their Ly-6C⁺ and CD5Low respective counterparts. Through comparison of RNASeq data, from these different CD4 TN cells populations, we have identified the transcription factors associated with their phenotypes. Among these factors, Foxo1- which is regulated by TCR signaling- is known to play a role in Treg differentiation. Our experiments have proven that the Tonic Signaling regulates via Foxo1 the ability of CD4 TN lymphocytes to differentiate into pTregs.The work done during my Phd thesis has therefore allowed a deeper understanding of the molecular pathways induced by the Tonic Signaling as well as its influence on the phenotype and function of naive CD4⁺ T cells.
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Submitted on : Thursday, November 5, 2020 - 11:45:26 AM
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Vincent Guichard. Influence des interactions avec le Soi sur le devenir des cellules T CD4 naïves en phase effectrice. Médecine humaine et pathologie. Université Paris Cité, 2019. Français. ⟨NNT : 2019UNIP7021⟩. ⟨tel-02989713⟩



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