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

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) generation in vitro. Whether and how C5aR2 impacts in vivo Tgeneration 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(iT) generation and that the absence of T cell-expressed C5aR2 limits in vivo iTgeneration following adoptive transfer of naive CD4T cells intorecipients. Using newly generated C5aR2-transgenic mice, we show that overexpression of C5aR2 in naive CD4T cells augments in vivo iTgeneration. In a model of T-dependent cardiac allograft survival, recipient C5aR2 deficiency accelerates graft rejection associated with lower T/effector T cell ratios, whereas overexpression of C5aR2 in immune cells prolongs graft survival associated with an increase in T/effector T cell ratios. T cell-expressed C5aR2 modulates Tinduction without altering effector T cell proliferation or cytokine production. Distinct from reported findings in neutrophils and macrophages, T-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 Tinduction. Together, the data expand the role of C5aR2 in adaptive immunity by providing in vivo evidence that T cell-expressed C5aR2 physiologically modulates iTgeneration and iT-dependent allograft survival

C5aR1 regulates T follicular helper differentiation and chronic graft-versus-host disease bronchiolitis obliterans

CD4+ follicular helper T (Tfh) cells are specialized providers of T cell help to B cells and can function as pathogenic mediators of murine antibody-dependent chronic graft-versus-host disease (GvHD). Using a parent→F1 model of lupus-like chronic GvHD, in which Tfh cell and germinal center (GC) B cell differentiation occurs over 14 days, we demonstrate that absence of CD4+ T cell-expressed C5a receptor 1 (C5ar1) or pharmacological C5aR1 blockade abrogated generation/expansion of Tfh cells, GC B cells, and autoantibodies. In a Tfh cell-dependent model of chronic GvHD manifested by bronchiolitis obliterans syndrome (BOS), C5aR1 antagonism initiated in mice with established disease ameliorated BOS and abolished the associated differentiation of Tfh and GC B cells. Guided by RNA-sequencing data, mechanistic studies performed using murine and human T cells showed that C5aR1 signaling amplifies IL-6-dependent expression of the transcription factor c-MAF and the cytokine IL-21 via phosphorylating phosphokinase B (AKT) and activating the mammalian target of rapamycin (mTOR). In addition to linking C5aR1-initiated signaling to Tfh cell differentiation, our findings suggest that C5aR1 may be a useful therapeutic target for prevention and/or treatment of individuals with Tfh cell-dependent diseases, including those chronic GvHD patients who have anti-host reactive antibodies