biostudies-literatureVerghese DANIDDK NIH HHSNIAID NIH HHSLeukemia Society of AmericaNCI NIH HHSNational Institutes of HealthNIH HHS124646https://www.ebi.ac.uk/biostudies/studies/S-EPMC6338317biostudies-literatureUnknown3(24)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.JCI insightC5aR1 regulates T follicular helper differentiation and chronic graft-versus-host disease bronchiolitis obliterans.PMC6338317P01 CA142106translational research grant 6458K08 AI135101R01 AI071185T32 AI078892P01 AI056299S10 OD018522R01 AI071185,P01 CA142106,P01 AI 056299,R01 HL11879,T32 DK007757,T32 AI078892.T32 DK007757Yi ZPaz KHu YWoodruff TMHeeger PSBlazar BRChun NVerghese DAZhang WFribourg MFlynn RDu JXiong HfalseC5aR1 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.2018-01-01T00:00:00Z2018 Dec2026-05-03T00:46:20.606Z2026-04-07T18:43:23.279ZS-EPMC63383173056803410.1172/jci.insight.124646