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

N. Chun,1 D. Verghese,1 M. Demir,1 M. Fribourg,3 I. Llaudo,1 E. Medof,4 P. Heeger.1

1Div of Nephrology, Dept of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, NY, NY
2Dept of Neurology, Icahn School of Medicine at Mount Sinai, NY, NY
3Dept of Pathology, Case Western Reserve Univ, Cleveland, OH.

Meeting: 2018 American Transplant Congress

Abstract number: 306

Keywords: Heart, T cells

Session Information

Date: Monday, June 4, 2018

Session Name: Concurrent Session: Innate Immunity; Chemokines, Cytokines, Complement

Session Time: 4:30pm-6:00pm

 Presentation Time: 5:18pm-5:30pm

Location: Room 618/619/620

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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 (iTREG) induction. We tested the hypothesis that C5aR2 modulates in vivo TREG generation and T cell-dependent allograft rejection. Flow cytometric image analyses showed that murine T cells express and upregulate C5aR2 during iTREG generation. After adoptive transfer of naïve WT-Foxp3RFP or C5aR2-/- Foxp3RFP CD4+ T cells into rag1-/-recipients we observed fewer Foxp3+ iTREG 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 iTREG 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 TREG/TEFF 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 TREG 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 TREG 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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To cite this abstract in AMA style:

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 [abstract]. https://atcmeetingabstracts.com/abstract/t-cell-expression-of-c5a-receptor-2-augments-murine-regulatory-t-cell-generation-and-regulatory-t-cell-dependent-cardiac-allograft-survival/. Accessed March 8, 2021.

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