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Role of CD27/CD70 pathway in regulatory T cells

par Bowakim, Natalia
Président du jury Vanhamme, Luc
Promoteur Moser, Muriel
Co-Promoteur Oldenhove, Guillaume
Publication Non publié, 2022-10-28

Thèse de doctorat

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Résumé :

Three different signals are necessary for the activation of T cells and therefore the development of an adaptive immune response. The first signal consists on the antigen presentation by dendritic cells (DCs) in the lymphoid organs in a Major Histocompatibility Complex (MHC) context to the antigen-specific TCR. The second one, via costimulatory molecules present on the surface of APCs and T cell receptors. Signal 3 is produced by the secretion of cytokines by APCs, which signal via cytokine receptors on T cells to polarize them toward an effector phenotype.CD70 and CD27, expressed mainly on antigen presenting cells and T lymphocytes, respectively, are members of the TNF/TNFR family. The CD27/CD70 pathway has been shown to trigger the differentiation of Th1- type CD4+ T lymphocytes. Of note, the sole expression of CD70 on immature DCs have been shown to break tolerance and induce immunity, underlying the critical role of CD70 in the regulation of immune responses in vivo.It has been shown that CD27, expressed at higher levels on Tregs, is also involved in the inhibition of inflammatory responses. Indeed, in our group Dhainaut and Moser have reported that regulatory T cells control Th1 priming by selectively inhibiting the expression of CD70 by DCs in a CD27-dependent manner. Intriguingly, these observations suggest that CD27 displays opposite functions, either inducing pro-inflammatory Th1 responses (when expressed on conventional T cells (Tconvs)) or inhibiting the inflammatory responses (when expressed on Tregs). The impact of CD27 engagement on Tconvs has been widely described but remains unknown for Tregs.The objective of this project was therefore to investigate the role of CD27 inthe function and homeostasis of Tregs in vivo, as compared to Tconvs.First, we described Tregs subsets expressing or lacking-CD27, and demonstrated that Tregs expressing CD27 exhibited an activated phenotype, suggesting that CD27 could be an activator marker for Tregs. Accordingly, we studied the function of Tregs lacking CD27 expression, and demonstrated that they presented an impaired suppression capacity. Second, we analyzed that CD27 engagement results in Treg expansion in vivo and increased expression of immunosuppressive molecules. Indeed, engagement with agonistic anti-CD27 mAb efficiently primed Tregs to an effector phenotype. Finally, to attempt to identify the role of CD27-engaged Tregs in vivo, we took advantage of CD11c-CD70tg;CD27+/- mice, and showed that Tregs converted into a Th1-like phenotype acquiring the expression of Tbet, CXCR3, Tigit and Eomes, and becoming effector Tregs as assessed by the increased production of IL-10 and IFN-γ. We also described the transcriptomic profile and demonstrated that despite displaying opposite functions the same signaling program was induced in Tconv compared to Tregs, triggering to a Th1 specialization.To further investigate the inhibitory function of CD27-engaged Tregs, experiments are under way to analyze Tregs function in various Th1 settings in vivo.