Session Time: 4:00pm-5:30pm
Presentation Time: 4:00pm-4:12pm
Location: Room 118-C
Tfh cells, in part via IL-6 dependent production of IL-21, are specialized providers of B cell help. Extending previous work in which we showed that signaling through C5aR expressed on T cells and antigen presenting cells (APCs) enhances alloreactive effector T cell proliferation, differentiation and expansion while inhibiting regulatory T cells (Treg), we assessed the impact of these signals on Tfh induction and function. When we stimulated WT and C5aR-/- CD4 T cells with anti-CD3/CD28, recombinant IL-6, and blocking anti-IFNg, anti-TGFb and anti-IL4 antibodies, we observed less IL-21 produced by C5aR-/- CD4 T cells (p=0.016 vs control). Because IL-6 signals via Stat3, we tested whether C5aR deficiency/blockade altered IL-6 induced Stat3 phosphorylation. These experiments showed decreased IL-6-induced pStat3 in C5aR-/- CD4 T cells vs. controls (p<0.05 at 15 and 30 min), and showed a dose dependent decrease in pStat3 when WT CD4 T cells were stimulated with IL-6 plus a specific C5aR antagonist (p<0.05). C5aR deficiency/blockade did not alter IL-10-induced Stat3 phosphorylation suggesting specificity for an IL-6/C5aR interaction. Expression of IL-6R and gp130 (IL-6 co-receptor) were similar on WT and C5aR-/- T cells. Together the results imply that C5aR expression enhances IL-6R signaling on T cells. To test effects of C5aR on Tfh cell induction and function in vivo we employed a Tfh-cell-dependent, lupus-like model of chronic graft versus host disease (cGVHD) that results in glomerulopathy: we adoptively transferred equal numbers of B6 WT or C5aR-/- CD4 T cells into (BALB/c x B6) F1 hosts. Two weeks later we observed that the recipients of C5aR-/- cells contained reduced numbers of donor derived Tfh cells (p=0.08) and recipient germinal center B cells (p=0.02) as well as decreased anti-dsDNA antibodies (p=0.04) vs. WT controls. The numbers of donor derived Foxp3+ follicular Treg were not different between groups. In separate experiments in which we followed animals (n=4-5/group) for 3 months post transfer we observed less hematuria and decreased histological evidence of glomerulopathy in recipients of C5aR-/- CD4 cells. Overall our data provide new mechanistic insight by showing that T cell expressed C5aR regulates IL-6 dependent induction and function of Tfh cells. The findings support the need for testing the efficacy of targeting C5aR to prevent allosensitization in the clinic.
To cite this abstract in AMA style:Verghese D, Heeger P. T Cell C5a Receptor (C5aR) Signaling Regulates T Follicular Helper Cell (Tfh) Induction [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/t-cell-c5a-receptor-c5ar-signaling-regulates-t-follicular-helper-cell-tfh-induction/. Accessed July 3, 2020.
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