Premium
Absence of recipient C3aR1 signaling limits expansion and differentiation of alloreactive CD8 + T cell immunity and prolongs murine cardiac allograft survival
Author(s) -
Mathern Douglas R.,
K. Horwitz Julian,
Heeger Peter S.
Publication year - 2019
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.15222
Subject(s) - cd8 , immunology , cytotoxic t cell , t cell , allorecognition , medicine , immune system , biology , microbiology and biotechnology , cancer research , biochemistry , in vitro
Activation, differentiation, and expansion of alloreactive CD8 + T cells, the dominant effectors that mediate murine heart allograft rejection, requires allorecognition, costimulation, and cytokine‐initiated signals. While previous work showed that alloreactive CD4 + T cell immunity entails immune cell‐produced and locally activated complement, whether and how C3a receptor 1 (C3aR1) signaling impacts transplant outcomes and the mechanisms linking C3aR1 to alloreactive CD8 + T cell activation/expansion remain unclear. Herein we show that recipient C3aR1 deficiency or pharmacological C3aR1 blockade synergizes with tacrolimus to significantly prolong allograft survival versus tacrolimus‐treated controls (median survival time 21 vs. 14 days, P < .05). Recipient C3aR1‐deficiency reduced the frequencies of posttransplant, donor‐reactive CD8 + T cells twofold. Reciprocal adoptive transfers of naive WT or C3ar1 −/− CD8 + T cells into syngeneic WT or C3ar1 −/− allograft recipients showed that T cell–expressed C3aR1 induces CD8 + T proliferation, mTOR activation and transcription factor T‐bet expression. Host C3aR1 indirectly facilitates alloreactive CD8 + T cell proliferation/expansion by amplifying antigen presenting cell costimulatory molecule expression and innate cytokine production. In addition to expanding mechanistic insight, our findings identify C3aR1 as a testable therapeutic target for future studies aimed at improving human transplant outcomes.