Type 1 regulatory T cells: cytotoxic activity and molecular signature

IL-10-producing CD4+ type 1 regulatory T (Tr1) cells, defined based on their ability to produce high levels of IL-10 in the absence of IL-4, are major players in the induction and maintenance of peripheral tolerance. Tr1 cells inhibit T cell responses mainly via cytokine dependent mechanisms. The cellular and molecular mechanisms underlying the suppression of APC by Tr1 cells are still not completely elucidated. Here, we defined that Tr1 cells specifically lyse myeloid APC through a granzyme B (GZB)- and perforin (PRF)- dependent mechanism that requires HLA class I recognition, CD54/Lymphocyte Function-associated Antigen (LFA)-1 adhesion, and activation via CD2. Notably, interaction between CD226 on Tr1 cells and their ligands on myeloid cells, leading to Tr1 cell activation, is necessary for defining Tr1 cell target specificity. We also showed that high frequency of GZB expressing CD4+ T cells is detected in tolerant patients and correlates with elevated occurrence of IL-10- producing CD4+ T cells. In conclusion, the modulatory activities of Tr1 cells are not only due to suppressive cytokines but also to specific cell-to-cell interactions which lead to selective killing of target cells and possibly bystander suppression. Adaptive type 1 regulatory T (Tr1) cells are suppressor cells characterized by the production of IL-10 in the absence of IL-4 and by the ability to suppress immune responses mainly by the release of IL- 10 and TGF-β. Despite several efforts for the detection of molecular markers of Tr1 cells have been made, so far Tr1 cell identification relies on cytokine production profile. Moreover, to date no master regulator gene for Tr1 cells have been defined. To identify Tr1 cell specific surface biomarkers, master regulator genes, and molecules involved in their suppressive functions, we performed a gene expression profiling to compare the gene expression of ex vivo isolated Tr1 cell clones compare to Th0 cell clones, in resting state and upon TCR activation. Results demonstrated that Tr1 cells signature is of anti-inflammation, anti-proliferation, and immuno-modulation. In addition, we identified surface molecules that could be useful to identify Tr1 cell population. Interestingly, several transcription factors resulted differentially expressed in Tr1 cells compared to Th0 cells, which may represent master regulators of Tr1 cells.