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

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2008 Mar 11

PMID 18328742

Citations 302

Authors

Michael G Strainic

Jinbo Liu

Danping Huang

Fengqi An

Peter N Lalli

Nasima Muqim

Virginia S Shapiro

George R Dubyak

Peter S Heeger

M Edward Medof

Affiliations

Soon will be listed here.

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-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.

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References

Morikis D, Lambris J . Structural aspects and design of low-molecular-mass complement inhibitors. Biochem Soc Trans. 2002; 30(Pt 6):1026-36. DOI: 10.1042/bst0301026. View

Alcazar I, Marques M, Kumar A, Hirsch E, Wymann M, Carrera A . Phosphoinositide 3-kinase gamma participates in T cell receptor-induced T cell activation. J Exp Med. 2007; 204(12):2977-87. PMC: 2118532. DOI: 10.1084/jem.20070366. View

Medof M, Kinoshita T, NUSSENZWEIG V . Inhibition of complement activation on the surface of cells after incorporation of decay-accelerating factor (DAF) into their membranes. J Exp Med. 1984; 160(5):1558-78. PMC: 2187498. DOI: 10.1084/jem.160.5.1558. View

Peng Q, Li K, Patel H, Sacks S, Zhou W . Dendritic cell synthesis of C3 is required for full T cell activation and development of a Th1 phenotype. J Immunol. 2006; 176(6):3330-41. DOI: 10.4049/jimmunol.176.6.3330. View

Kopf M, Abel B, Gallimore A, Carroll M, Bachmann M . Complement component C3 promotes T-cell priming and lung migration to control acute influenza virus infection. Nat Med. 2002; 8(4):373-8. DOI: 10.1038/nm0402-373. View

Heeger P, Lalli P, Lin F, Valujskikh A, Liu J, Muqim N . Decay-accelerating factor modulates induction of T cell immunity. J Exp Med. 2005; 201(10):1523-30. PMC: 2212927. DOI: 10.1084/jem.20041967. View

Lin F, Fukuoka Y, Spicer A, Ohta R, Okada N, Harris C . Tissue distribution of products of the mouse decay-accelerating factor (DAF) genes. Exploitation of a Daf1 knock-out mouse and site-specific monoclonal antibodies. Immunology. 2001; 104(2):215-25. PMC: 1783297. DOI: 10.1046/j.1365-2567.2001.01287.x. View

Sasaki T, Irie-Sasaki J, Jones R, Stanford W, Bolon B, Wakeham A . Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration. Science. 2000; 287(5455):1040-6. DOI: 10.1126/science.287.5455.1040. View

Diehl L, den Boer A, van der Voort E, Melief C, Offringa R, Toes R . The role of CD40 in peripheral T cell tolerance and immunity. J Mol Med (Berl). 2000; 78(7):363-71. DOI: 10.1007/s001090000126. View

10.

Stein P, Fraser J, Weiss A . The cytoplasmic domain of CD28 is both necessary and sufficient for costimulation of interleukin-2 secretion and association with phosphatidylinositol 3'-kinase. Mol Cell Biol. 1994; 14(5):3392-402. PMC: 358704. DOI: 10.1128/mcb.14.5.3392-3402.1994. View

11.

Cain S, Monk P . The orphan receptor C5L2 has high affinity binding sites for complement fragments C5a and C5a des-Arg(74). J Biol Chem. 2002; 277(9):7165-9. DOI: 10.1074/jbc.C100714200. View

12.

Lenschow D, Zeng Y, Hathcock K, Zuckerman L, Freeman G, Thistlethwaite J . Inhibition of transplant rejection following treatment with anti-B7-2 and anti-B7-1 antibodies. Transplantation. 1995; 60(10):1171-8. DOI: 10.1097/00007890-199511270-00019. View

13.

Liu C, Fan Y, Dias A, Esper L, Corn R, Bafica A . Cutting edge: dendritic cells are essential for in vivo IL-12 production and development of resistance against Toxoplasma gondii infection in mice. J Immunol. 2006; 177(1):31-5. DOI: 10.4049/jimmunol.177.1.31. View

14.

Goruppi S, Ruaro E, Varnum B, Schneider C . Requirement of phosphatidylinositol 3-kinase-dependent pathway and Src for Gas6-Axl mitogenic and survival activities in NIH 3T3 fibroblasts. Mol Cell Biol. 1997; 17(8):4442-53. PMC: 232298. DOI: 10.1128/MCB.17.8.4442. View

15.

Kang Y, Do Y, Lee H, Park S, Cheong C, Lynch R . A dominant complement fixation pathway for pneumococcal polysaccharides initiated by SIGN-R1 interacting with C1q. Cell. 2006; 125(1):47-58. DOI: 10.1016/j.cell.2006.01.046. View

16.

Kane L, Andres P, Howland K, Abbas A, Weiss A . Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN-gamma but not TH2 cytokines. Nat Immunol. 2001; 2(1):37-44. DOI: 10.1038/83144. View

17.

Soruri A, Kim S, Kiafard Z, Zwirner J . Characterization of C5aR expression on murine myeloid and lymphoid cells by the use of a novel monoclonal antibody. Immunol Lett. 2003; 88(1):47-52. DOI: 10.1016/s0165-2478(03)00052-x. View

18.

Wenderfer S, Ke B, Hollmann T, Wetsel R, Lan H, Braun M . C5a receptor deficiency attenuates T cell function and renal disease in MRLlpr mice. J Am Soc Nephrol. 2005; 16(12):3572-82. DOI: 10.1681/ASN.2005040373. View

19.

Kung C, Kenski D, Krukenberg K, Madhani H, Shokat K . Selective kinase inhibition by exploiting differential pathway sensitivity. Chem Biol. 2006; 13(4):399-407. PMC: 2932700. DOI: 10.1016/j.chembiol.2006.02.004. View

20.

Huber-Lang M, Sarma J, Zetoune F, Rittirsch D, Neff T, McGuire S . Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med. 2006; 12(6):682-7. DOI: 10.1038/nm1419. View