Mechanisms of IL-10 production in human microglia-T cell interaction.
IL-10, a cytokine with important anti-inflammatory properties, is generated within the CNS during neuroinflammation. The mechanism for its production is poorly understood. Since infiltrating lymphocytes come into close proximity with the macrophage-like cells of the CNS, the microglia, we have used an in vitro human microglia-T cell coculture system to address the mechanisms of IL-10 production. We demonstrate that microglia or activated T cells alone secrete negligible amounts of IL-10, but that their coculture results in significant IL-10 production, which was effected by both cell types. IL-10 generation was cell contact dependent, and treatment with anti-CD40, CTLA-4-Fc, or anti-CD23 decreased the IL-10 content in microglia-T cell cocultures. The combination of anti-CD40 and CTLA-4-Fc reduced IL-10 levels to the negligible amounts seen with T cells or microglia in isolation. By also measuring TNF-alpha levels, specificity of cytokine regulation was observed; while anti-CD40 and CTLA-4-Fc reduced IL-10 and TNF-alpha levels, anti-CD23 did not affect TNF-alpha while attenuating IL-10 generation. Anti-very late Ag-4, which decreased TNF-alpha levels, did not affect IL-10. These results implicate the CD40, B7, and CD23 pathways in IL-10 production following microglia-T cell encounter and have relevance to the regulation of an anti-inflammatory response within the CNS.
Chabot
S
S
Department of Oncology, University of Calgary, Alberta, Canada.
Williams
G
G
Hamilton
M
M
Sutherland
G
G
Yong
V W
VW
D000069594:Abatacept; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen; D002450:Cell Communication / Q000276:immunology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018920:Coculture Techniques; D004357:Drug Synergism; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D018796:Immunoconjugates; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D017628:Microglia / Q000276:immunology* / Q000378:metabolism*; D017455:Receptors, IgE / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D007106:Immune Sera; D018796:Immunoconjugates; D017455:Receptors, IgE; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000069594:Abatacept