Decay accelerating factor can control T cell differentiation into IFN-gamma-producing effector cells via regulating local C5a-induced IL-12 production.
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-gamma compared with cultures containing wild-type APCs. DAF-regulated IL-12 production and subsequent T cell differentiation into IFN-gamma-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-gamma. Bone marrow chimera experiments verified that bone marrow cell-expressed C5aR is required for optimal differentiation into IFN-gamma-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-gamma-producing phenotype. The findings have implications for design of therapies aimed at altering pathologic T cell immunity.
Lalli
Peter N
PN
Department of Immunology, Cleveland Clinic, Cleveland, OH 44195, USA.
Strainic
Michael G
MG
Lin
Feng
F
Medof
M Edward
ME
Heeger
Peter S
PS
D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D018958:CD55 Antigens / Q000235:genetics / Q000378:metabolism*; D015936:Complement C5a / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D019891:Leukopoiesis / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053707:Receptors, Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
D018958:CD55 Antigens; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D015936:Complement C5a; D007371:Interferon-gamma