T cell expression of C5a receptor 2 augments murine regulatory T cell generation and regulatory-T-cell-dependent cardiac allograft survival

C5aR2 (C5L2/gp77) is a 7-transmembrane spanning receptor that binds to C5a but lacks motifs essential for G-protein coupling and associated signal transduction. C5aR2 is expressed on immune cells, modulates various inflammatory diseases in mice, and has been shown to facilitate murine and human regulatory T cell (iT REG ) generation in vitro . Whether and if so how, C5aR2 impacts in vivo T REG generation and pathogenic T cell-dependent disease models have not been established. Herein we show that murine T cells express and upregulate C5aR2 during iT REG generation and that the absence of T cell-expressed C5aR2 limits in vivo iT REG generation following adoptive transfer of naïve CD4 + T cells into rag1 −/− recipients. Using newly generated C5aR2 transgenic mice (C5aR2-tg) we show that overexpression of C5aR2 in naïve CD4 + T cells augments in vivo iT REG generation. In a model of T REG -dependent cardiac allograft survival, recipient C5aR2 deficiency accelerates graft rejection associated with lower T REG /T EFF ratios while overexpression of C5aR2 in immune cells prolongs graft survival associated with an elevation in T REG /T EFF ratios. T cell-expressed C5aR2 modulates T REG induction without altering effector T cell proliferation or cytokine production. Distinct from reported findings in neutrophils and macrophages, T REG -expressed C5aR2 does not interact with β-arrestin or inhibit ERK1/2 signaling. Rather, cumulative evidence supports the conclusion that C5aR2 limits C5aR1-initiated signals known to inhibit T REG induction. Together, the data expand the role of C5aR2 in adaptive immunity by providing in vivo evidence that T cell-expressed C5aR2 physiologically modulates iT REG generation and iT REG -dependent allograft survival.