Verghese DA, Chun N, Paz K, Fribourg M, Woodruff TM, Flynn R, Hu Y, Xiong H, Zhang W, Yi Z, Du J, Blazar BR, Heeger PS. 2018. C5aR1 regulates T follicular helper differentiation and chronic graft-versus-host disease bronchiolitis obliterans. JCI insight. 3(24). Pubmed: 30568034 DOI:10.1172/jci.insight.124646


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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Ryan Flynn’s laboratory is focused on the exploration and discovery of how biopolymers like RNA and glycans work together to control cellular processes in the context of human disease.

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