Locally Produced Complement Fragments C5a and C3a Provide Both Costimulatory and Survival Signals to Naive CD4+ T Cells

Michael G. Strainic, Jinbo Liu, Danping Huang, Fengqi An, Peter N. Lalli, Nasima Muqim, Virginia S. Shapiro, George R R. Dubyak, Peter S. Heeger, M. Edward Medof

Research output: Contribution to journalArticle

355 Scopus citations

Abstract

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-γ-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.

Original languageEnglish (US)
Pages (from-to)425-435
Number of pages11
JournalImmunity
Volume28
Issue number3
DOIs
StatePublished - Mar 14 2008

Keywords

  • MOLIMMUNO

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Strainic, M. G., Liu, J., Huang, D., An, F., Lalli, P. N., Muqim, N., Shapiro, V. S., Dubyak, GR. R., Heeger, P. S., & Medof, M. E. (2008). Locally Produced Complement Fragments C5a and C3a Provide Both Costimulatory and Survival Signals to Naive CD4+ T Cells. Immunity, 28(3), 425-435. https://doi.org/10.1016/j.immuni.2008.02.001