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

Divya A. Verghese, Markus Demir, Nicholas Chun, Miguel Fribourg, Paolo Cravedi, Ines Llaudo, Trent M. Woodruff, Pragya Yadav, Sergio A. Lira, M. Edward Medof, Peter S. Heeger

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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 (TREG) generation in vitro. Whether and how C5aR2 impacts in vivo TREG 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 TREG (iTREG) generation and that the absence of T cell- expressed C5aR2 limits in vivo iTREG 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 iTREG generation. In a model of TREG-dependent cardiac allograft survival, recipient C5aR2 deficiency accelerates graft rejection associated with lower TREG/effector T cell ratios, whereas overexpression of C5aR2 in immune cells prolongs graft survival associated with an increase in TREG/effector T cell ratios. T cell-expressed C5aR2 modulates TREG induction without altering effector T cell proliferation or cytokine production. Distinct from reported findings in neutrophils and macrophages, TREGexpressed 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 TREG induction. Together, the data expand the role of C5aR2 in adaptive immunity by providing in vivo evidence that T cell-expressed C5aR2 physiologically modulates iTREG generation and iTREG-dependent allograft survival.

Original languageEnglish
Pages (from-to)2186-2198
Number of pages13
JournalJournal of Immunology
Issue number6
StatePublished - 15 Mar 2018


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