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

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.

SUBMITTER: Mathern DR

PROVIDER: S-EPMC6538425 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Mathern Douglas R DR Horwitz Julian K JK Heeger Peter S PS

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20190114 6

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<sup ...[more]

PMID: 30565852

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Project description:Selectively depleting the pathogenic T cells is a fundamental strategy for the treatment of allograft rejection and autoimmune disease since it retains the overall immune function of host. The concept of killer artificial antigen-presenting cells (KaAPCs) has been developed by co-coupling peptide-major histocompatibility complex (pMHC) multimer and anti-Fas monoclonal antibody (mAb) onto the polymeric microparticles (MPs) to induce the apoptosis of antigen-specific T cells. But little information is available about its in vivo therapeutic potential and mechanism. In this study, polyethylenimine (PEI)-coated poly lactic-co-glycolic acid microparticle (PLGA MP) was fabricated as a cell-sized scaffold to covalently co-couple H-2Kb-Ig dimer and anti-Fas mAb for the generation of alloantigen-presenting and apoptosis-inducing MPs. Intravenous infusions of the biodegradable KaAPCs prolonged the alloskin graft survival for 43 days in a single MHC-mismatched murine model, depleted the most of H-2Kb-alloreactive CD8+ T cells in peripheral blood, spleen, and alloskin graft in an antigen-specific manner and anti-Fas-dependent fashion. The cell-sized KaAPCs circulated throughout vasculature into liver, kidney, spleen, lymph nodes, lung, and heart, but few ones into local allograft at early stage, with a retention time up to 36 h in vivo. They colocalized with CD8+ T cells in secondary lymphoid organs while few ones contacted with CD4+ T cells, B cells, macrophage, and dendritic cells, or internalized by phagocytes. Importantly, the KaAPC treatment did not significantly impair the native T cell repertoire or non-pathogenic immune cells, did not obviously suppress the overall immune function of host, and did not lead to visible organ toxicity. Our results strongly document the high potential of PLGA MP-based KaAPCs as a novel antigen-specific immunotherapy for allograft rejection and autoimmune disorder. The in vivo mechanism of alloinhibition, tissue distribution, and biosafety were also initially characterized, which will facilitate its translational studies from bench to bedside.

Dataset Information

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

Publications

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

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