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-Producing Effector Cells via Regulating Local C5a-Induced IL-12 Production1
,
* Department of Immunology, Cleveland Clinic, Cleveland, OH 44195;
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106; and
Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029
A newly recognized link between the complement system and adaptive immunity is that decay accelerating factor (DAF), a cell surface C3/C5 convertase regulator, exerts control over T cell responses. Extending these results, we show that cultures of Marilyn TCR-transgenic T cells stimulated with DAF-deficient (Daf1–/–) APCs produce significantly more IL-12, C5a, and IFN-
compared with cultures containing wild-type APCs. DAF-regulated IL-12 production and subsequent T cell differentiation into IFN--producing effectors was prevented by the deficiency of either C3 or C5a receptor (C5aR) in the APC, demonstrating a link between DAF, local complement activation, IL-12, and T cell-produced IFN-. Bone marrow chimera experiments verified that bone marrow cell-expressed C5aR is required for optimal differentiation into IFN--producing effector T cells. Overall, our results indicate that APC-expressed DAF regulates local production/activation of C5a following cognate T cell/APC interactions. Through binding to its receptor on APCs the C5a up-regulates IL-12 production, this in turn, contributes to directing T cell differentiation toward an IFN--producing phenotype. The findings have implications for design of therapies aimed at altering pathologic T cell immunity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AI43578 (to P.S.H.) and AI23598 (to M.E.M.) and by a grant from the Roche Organ Transplant Research Fund (to P.S.H.). P.N.L. received a fellowship grant from the Ohio Affiliate of the American Heart Association.
2 Address correspondence and reprint requests to Dr. Peter S. Heeger, Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, Annenberg 23 66 B Box 1243, One Gustave Levy Place, New York, NY 10029. E-mail address: peter.heeger{at}mssm.edu
3 Abbreviations used in this paper: DAF, decay accelerating factor; WT, wild type.
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