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

ABSTRACT: The goal of the study was to determine the effect of T cell expressed C5ar1 on transcriptional profiles of in vivo generated allogeneic T follicular helper cells

ORGANISM(S): Mus musculus

PROVIDER: GSE121796 | GEO | 2019/01/01

REPOSITORIES: GEO

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

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

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

Project description: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.

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