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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 (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, TREG-expressed C5aR2 does not interact with ?-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.

SUBMITTER: A Verghese D

PROVIDER: S-EPMC5894525 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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

A Verghese Divya D Demir Markus M Chun Nicholas N Fribourg Miguel M Cravedi Paolo P Llaudo Ines I Woodruff Trent M TM Yadav Pragya P Lira Sergio A SA Medof M Edward ME Heeger Peter S PS

Journal of immunology (Baltimore, Md. : 1950) 20180207 6

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 t ...[more]

PMID: 29436411

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Dataset Information

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

Publications

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

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