Immune cell-derived C3a and C5a costimulate human T cell alloimmunity

Am J Transplant. 2013 Oct;13(10):2530-9. doi: 10.1111/ajt.12405. Epub 2013 Sep 6.

Abstract

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 in vitro 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(+) 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 scid γc(null) mouse recipients of human peripheral blood mononuclear cells, verifying that the mechanisms apply in vivo. 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.

Trial registration: ClinicalTrials.gov NCT01363388.

Keywords: AKT; C3; C5; GVHD; T cells; complement; dendritic cells; transplant.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Blotting, Western
  • Cell Proliferation
  • Complement C3a / immunology*
  • Complement C3a / metabolism
  • Complement C5a / immunology*
  • Complement C5a / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Graft vs Host Disease / immunology*
  • Graft vs Host Disease / prevention & control
  • Humans
  • Leukocytes, Mononuclear / immunology*
  • Leukocytes, Mononuclear / metabolism
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptor, Anaphylatoxin C5a / immunology*
  • Receptor, Anaphylatoxin C5a / metabolism
  • Receptors, Complement / immunology*
  • Receptors, Complement / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • C5AR1 protein, human
  • RNA, Messenger
  • Receptor, Anaphylatoxin C5a
  • Receptors, Complement
  • complement C3a receptor
  • Complement C3a
  • Complement C5a

Associated data

  • ClinicalTrials.gov/NCT01363388