Induction of CD4+ regulatory T cells by soluble HLA-G isoforms.

Abstract

Purpose/Objective: The non-classical HLA class I molecule HLA-G was initially shown to play a major role in feto-maternal tolerance. Since this discovery, it has been established that HLA-G is a tolerogenic molecule, which participates to the control of the immune response. HLA-G inhibits a wide array of immune cells and has long-term immune- modulatory effects since it can induce the generation of suppressor/ regulatory cells. We recently demonstrated that tolerogenic DC, termed DC-10, promote the differentiation of Tr1 cells via the IL10-dependent membrane bound HLA-G1/ILT4 pathway. The role of membrane-bound HLA-G1 in promoting Tr1 cells via DC-10, raise the question whether soluble shed HLA-G1 or HLA-G5 can promote Tr1 cell differentiation. Materials and methods: Human naı¨ve CD4+ T cells were stimulated via anti-CD3 mAbs cross-linked on artificial APC consisting in murine L-cells co-transfected with human CD32, CD80, and CD58 in the presence of shed sHLA-G1 or HLA-G5 alone or in combination with IL-10. As control, we used Th0 and Tr1 cells differentiated with artificial APC alone or in the presence of IL-10 and IFN-a, respectively. Results: We showed that repetitive stimulation of human naı¨ve CD4+ T cells in the presence of shed HLA-G1 or HLA-G5, alone or in combination with IL-10, induced the differentiation of a population of CD4+ T cells that are phenotypically different from both Th0 and Tr1 cells. T cells differentiated with soluble HLA-Gs secrete lower levels of IFN-g and IL-2 as compared to Th0 cells. Interestingly, HLA-Ginduced T cells secrete low amounts of IL-10, which is slightly increased when IL-10 is present in culture, but never reach the levels produced by Tr1 cells. Despite the ability to proliferate upon polyclonal activation, HLA-G-induced T cells suppress the proliferation of autologous CD4+ T cells in vitro. Conclusions: We showed that activation of human CD4+ T cells in the presence of both soluble shed HLA-G1 or HLA-G5, alone or in combination with IL-10, promotes the induction of a population of suppressor CD4+ T cells, which are distinct from Tr1 cells

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