Locally produced C5a binds to T cell-expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis

Blood. 2008 Sep 1;112(5):1759-66. doi: 10.1182/blood-2008-04-151068. Epub 2008 Jun 20.

Abstract

Our recent studies have shown that immune cell-produced complement provides costimulatory and survival signals to naive CD4(+) T cells. Whether these signals are similarly required during effector cell expansion and what molecular pathways link locally produced complement to T-cell survival were not clarified. To address this, we stimulated monoclonal and polyclonal T cells in vitro and in vivo with antigen-presenting cells (APCs) deficient in the complement regulatory protein, decay accelerating factor (DAF), and/or the complement component C3. We found that T-cell expansion induced by DAF-deficient APCs was augmented with diminished T-cell apoptosis, whereas T-cell expansion induced by C3(-/-) APCs was reduced because of enhanced T-cell apoptosis. These effects were traced to locally produced C5a, which through binding to T cell-expressed C5aR, enhanced expression of Bcl-2 and prevented Fas up-regulation. The results show that C5aR signal transduction in T cells is important to allow optimal T-cell expansion, as well as to maintain naive cell viability, and does so by suppressing programmed cell death.

Publication types

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

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology
  • Apoptosis / immunology
  • CD55 Antigens / genetics
  • CD55 Antigens / metabolism
  • Cell Survival / immunology
  • Class Ib Phosphatidylinositol 3-Kinase
  • Complement Activation
  • Complement C3 / genetics
  • Complement C3 / metabolism
  • Complement C5a / biosynthesis
  • Complement C5a / metabolism*
  • Isoenzymes / metabolism
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • Mice, Knockout
  • Mice, Transgenic
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptor, Anaphylatoxin C5a / deficiency
  • Receptor, Anaphylatoxin C5a / genetics
  • Receptor, Anaphylatoxin C5a / metabolism*
  • Signal Transduction
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • fas Receptor / metabolism

Substances

  • CD55 Antigens
  • Complement C3
  • Fas protein, mouse
  • Isoenzymes
  • Proto-Oncogene Proteins c-bcl-2
  • Receptor, Anaphylatoxin C5a
  • decay-accelerating factor 1, mouse
  • fas Receptor
  • Complement C5a
  • Phosphatidylinositol 3-Kinases
  • Class Ib Phosphatidylinositol 3-Kinase
  • Pik3cg protein, mouse