Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells.
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.
Strainic
Michael G
MG
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Liu
Jinbo
J
Huang
Danping
D
An
Fengqi
F
Lalli
Peter N
PN
Muqim
Nasima
N
Shapiro
Virginia S
VS
Dubyak
George R
GR
Heeger
Peter S
PS
Medof
M Edward
ME
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival / Q000276:immunology*; D015926:Complement C3a / Q000276:immunology* / Q000378:metabolism; D015936:Complement C5a / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D015151:Immunoblotting; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D044087:Receptor, Anaphylatoxin C5a / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
D018122:B7-1 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; D012333:RNA, Messenger; D044087:Receptor, Anaphylatoxin C5a; D023201:CD40 Ligand; D015926:Complement C3a; D015936:Complement C5a