C5aR2 (C5L2/gp77) is a transmembrane receptor that binds C5a but lacks motifs needed to induce G-protein coupled signal transduction. C5aR2 modulates various inflammatory diseases in mice and has been shown to facilitate in vitro regulatory T cell (iT_REG) induction. We tested the hypothesis that C5aR2 modulates in vivo T_REG generation and T cell-dependent allograft rejection. Flow cytometric image analyses showed that murine T cells express and upregulate C5aR2 during iT_REG generation. After adoptive transfer of naïve WT-Foxp3RFP or C5aR2^-/- Foxp3RFP CD4⁺ T cells into rag1^-/-recipients we observed fewer Foxp3⁺ iT_REG in the C5aR2^-/- cells (1.9 v 4 per 1×10⁶ splenocytes. C5aR2^-/ vs WT, p<0.05, n=4-5/grp). Using newly generated C5aR2 transgenic mice (C5aR2-tg) we conversely find that overexpression of C5aR2 in CD4⁺ T cells augmented in vivo iT_REG generation after analogous transfer of naïve CD4⁺ T cells into rag1^-/- recipients (204.6 v 32.16 per 1×10⁶ splenocytes. C5aR2-tg vs WT, p<0.05, n=4-5/grp). In a transplant model, MR1-treated B6 C5aR2^-/- mice rejected MHC-disparate BALB/c hearts faster than MR1-treated WT recipients (MST 30d v 50d, p<0.05, n=7-9/grp). At 20d posttransplant this was associated with a higher frequency of donor reactive T cells (90.1 v 6.1 IFNg producers/1×10⁶ splenocytes, C5aR2^-/- vs WT, p<0.05) and diminished splenic T_REG/T_EFF ratios (0.15×10⁵ v 2.2×10⁵ C5aR2^-/- vs WT, p<0.05). Conversely, MR1-treated C5aR2-tg recipients rejected BALB/c hearts with delayed kinetics (MST >100 days, p<0.05 vs WT) and at 28d posttransplant had fewer donor-reactive T cells (309 v 128 per 1×10⁶ splenocytes. WT vs C5aR2-tg, p<0.05, n=4-5/grp) and higher Treg/Teff ratios (273.2 v 126.9 C5aR2^-/ vs WT, p<0.05). Mechanistic studies showed that Tcell-expressed C5aR2 limits C5aR1-initiated signals (pAKT and p-pS6) known to inhibit T_REG induction. Our findings add to the increasingly recognized function of the complement system as a modulator of adaptive T cell immunity and provide the foundation for designing therapeutics that upregulate T cell C5aR2 to increase T_REG generation and suppress pathogenic T cell immunity, including those induced by transplantation.

CITATION INFORMATION: Chun N., Verghese D., Demir M., Fribourg M., Llaudo I., Medof E., Heeger P. T-Cell Expression of C5a Receptor 2 Augments Murine Regulatory T Cell Generation and Regulatory-T-Cell-Dependent Cardiac Allograft Survival Am J Transplant. 2017;17 (suppl 3).

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