Immune Cell‐Derived C3a and C5a Costimulate Human T Cell Alloimmunity. Issue 10 (6th September 2013)

• Record Type: Journal Article
• Authors: Cravedi, P.; Leventhal, J.; Lakhani, P.; Ward, S. C.; Donovan, M. J.; Heeger, P. S.
• Is Part Of: American journal of transplantation. Volume 13:Issue 10(2013)
• Page Start: 2530
• Page End: 2539
• Publication Date: 2013-09-06
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; 617.95
• DOI: 10.1111/ajt.12405
• Languages: English
• ISSNs: 1600-6135

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="ajt12405-sec-0001" sec-type="section"> <p>Emerging evidence indicates that complement provides costimulatory signals for murine T cells but whether complement impacts human T cells remains unclear. We observed production of complement activation products C3a and C5a during <italic>in vitro</italic> cultures of human T cells responding to allogeneic dendritic cells (DC). Both partners expressed the receptors for C3a (C3aR) and C5a (C5aR) and C3aR‐ and C5aR‐antagonists inhibited T cell proliferation. Recombinant C3a/C5a promoted CD4<sup>+</sup> T cell expansion, bypassed the inhibitory effects of CTLA4‐Ig, and induced AKT phosphorylation, the latter biochemically linking C3aR/C5aR to known T cell signaling pathways. Lowering DC C3a/C5a production by siRNA knockdown of DC C3 reduced T cell alloresponses. Conversely downregulating DC expression of the complement regulatory protein decay–accelerating factor increased immune cell C3a/C5a and augmented T cell proliferation, identifying antigen presenting cells as the dominant complement source. Pharmacological C5aR blockade reduced graft versus host disease (GVHD) scores, prolonged survival, and inhibited T cell responses in NOD <italic>scid</italic> γc<sup>null</sup> mouse recipients of human peripheral blood mononuclear cells, verifying that the mechanisms apply <italic>in vivo</italic>. Together our findings unequivocally document that immune cell–derived complement impacts human T cell immunity and provide the foundation for future studies targeting C3aR/C5aR as treatments of GVHD and organ transplant rejection in humans.</p> </sec> </abstract>