T Cell Expression of C5a Receptor 2 Augments Murine Regulatory T Cell (T) Generation and T-Dependent Cardiac Allograft Survival.

C5aR2 (C5L2/gp77) is a seven-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 (T) generation in vitro. Whether and how C5aR2 impacts in vivo T generation and pathogenic T cell-dependent disease models have not been established. In this article, we show that murine T cells express and upregulate C5aR2 during induced T (iT) generation and that the absence of T cell-expressed C5aR2 limits in vivo iT generation following adoptive transfer of naive CD4 T cells into recipients. Using newly generated C5aR2-transgenic mice, we show that overexpression of C5aR2 in naive CD4 T cells augments in vivo iT generation. In a model of T-dependent cardiac allograft survival, recipient C5aR2 deficiency accelerates graft rejection associated with lower T/effector T cell ratios, whereas overexpression of C5aR2 in immune cells prolongs graft survival associated with an increase in T/effector T cell ratios. T cell-expressed C5aR2 modulates T induction without altering effector T cell proliferation or cytokine production. Distinct from reported findings in neutrophils and macrophages, T-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 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 generation and iT-dependent allograft survival.