Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells

Immunity. 2008 Mar;28(3):425-35. doi: 10.1016/j.immuni.2008.02.001. Epub 2008 Mar 6.


Costimulatory signals are critical to T cell activation, but how their effects are mediated remains incompletely characterized. Here, we demonstrate that locally produced C5a and C3a anaphylatoxins interacting with their G protein-coupled receptors (GPCRs), C5aR and C3aR, on APCs and T cells both upstream and downstream of CD28 and CD40L signaling are integrally involved in T cell proliferation and differentiation. Disabling these interactions reduced MHC class II and costimulatory-molecule expression and dramatically diminished T cell responses. Importantly, impaired T cell activation by Cd80-/-Cd86-/- and Cd40-/- APCs was reconstituted by added C5a or C3a. C5aR and C3aR mediated their effects via PI-3 kinase-gamma-dependent AKT phosphorylation, providing a link between GPCR signaling, CD28 costimulation, and T cell survival. These local paracrine and autocrine interactions thus operate constitutively in naive T cells to maintain viability, and their amplification by cognate APC partners thus is critical to T cell costimulation.

Publication types

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

MeSH terms

  • Animals
  • Antigen Presentation / immunology
  • Antigen-Presenting Cells / immunology
  • B7-1 Antigen / immunology
  • B7-1 Antigen / metabolism
  • CD28 Antigens / immunology
  • CD28 Antigens / metabolism
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD40 Antigens / immunology
  • CD40 Antigens / metabolism
  • CD40 Ligand / immunology
  • CD40 Ligand / metabolism
  • Cell Differentiation / immunology
  • Cell Survival / immunology*
  • Complement C3a / immunology*
  • Complement C3a / metabolism
  • Complement C5a / immunology*
  • Complement C5a / metabolism
  • Flow Cytometry
  • Immunoblotting
  • Immunoprecipitation
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Transgenic
  • Polymerase Chain Reaction
  • RNA, Messenger / analysis
  • Receptor, Anaphylatoxin C5a / immunology
  • Receptor, Anaphylatoxin C5a / metabolism
  • Signal Transduction / immunology


  • B7-1 Antigen
  • CD28 Antigens
  • CD40 Antigens
  • RNA, Messenger
  • Receptor, Anaphylatoxin C5a
  • CD40 Ligand
  • Complement C3a
  • Complement C5a