Absence of recipient C3aR1 signaling limits expansion and differentiation of alloreactive CD8+ T cell immunity and prolongs murine cardiac allograft survival

Douglas R. Mathern, Julian K. Horwitz, Peter S. Heeger

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1628-1640
Number of pages13
JournalAmerican Journal of Transplantation
Volume19
Issue number6
DOIs
StatePublished - Jun 2019

Keywords

  • T cell biology
  • animal models: murine
  • basic (laboratory) research/science
  • complement biology
  • immunobiology
  • immunosuppressant - calcineurin inhibitor (CNI)

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