IL-10-Dependent Infectious Tolerance after the Treatment of Experimental Allergic Encephalomyelitis with Redirected CD4+CD25+T Lymphocytes

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 33; pp. 11817 - 11822
• Main Authors: Mekala, Divya J., Alli, Rajshekhar S., Geiger, Terrence L., Flavell, Richard A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 16-08-2005; National Acad Sciences
• Subjects: Allergies; Animals; Antibodies; Antigens; Biological Sciences; CD4-Positive T-Lymphocytes - immunology; Cell Proliferation; Cultured cells; Cytokines; Cytokines - immunology; Drug regulation; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Female; Government regulation; Immune Tolerance - immunology; Immunization; Immunology; Immunotherapy; Infections - immunology; Infections - pathology; Interleukin-10 - immunology; Mice; Pathology; Receptors; Receptors, Interleukin-2 - immunology; T lymphocytes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0505445102

How small numbers of CD4+CD25+regulatory T cells suppress autoimmune responses in vivo is unclear. In this report we analyze the immunomodulatory activity of CD4+CD25+T cells that are antigen-specifically redirected against myelin basic protein (MBP)89-101-specific autoreactive T cells by a MBP89-101- IAs-ζ chimeric receptor. We have previously shown that these redirected regulatory T cells are highly potent in treating a model autoimmune disease, experimental allergic encephalomyelitis. We show here that they have only limited effect in vivo on autoreactive T cell proliferation and therefore do not act by deleting or suppressing the expansion of pathologic effector cells. Rather, the redirected CD4+CD25+T cells divert the pathologic T helper 1 self-specific T cell response to one characterized by high IL-10 and lower IL-4 production. Significantly, when isolated from the inducing CD4+CD25+regulatory T cells, these self-specific T cells can independently suppress the autoreactive T cell response and experimental allergic encephalomyelitis development in an IL-10-dependent manner. These results provide evidence that CD4+CD25+regulatory T cells can manipulate the adaptive immune response in vivo through the infectious induction of tolerance, specifically by promoting the formation of antigen-specific, IL-10-secreting regulatory T cells.