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

Abstract

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_REG) generation in vitro. Whether and how C5aR2 impacts in vivo T_REG 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_REG (iT_REG) generation and that the absence of T cell-expressed C5aR2 limits in vivo iT_REG generation following adoptive transfer of naive CD4⁺ T cells into Rag1^-/- recipients. Using newly generated C5aR2-transgenic mice, we show that overexpression of C5aR2 in naive 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/effector T cell ratios, whereas overexpression of C5aR2 in immune cells prolongs graft survival associated with an increase in T_REG/effector T cell 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.