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Variable Effects of Transgenic c-Maf on Autoimmune Diabetes

From the Department of Immunology (M.E.P., A.N., D.L.) and the Department of Neuropharmacology (T.W., M.v.H.), Division of Virology, The Scripps Research Institute; Integrative Biology (D.L.), Digital Gene Technologies, La Jolla, California; the Department of Immunology and Infectious Diseases (I.-C.H., L.H.G.), Harvard School of Public Health; and the Department of Medicine (L.H.G.), Harvard Medical School, Boston, Massachusetts. The present affiliation for M.E.P. is the Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois.

Address correspondence and reprint requests to Dr. David Lo, Integrative Biology, Digital Gene Technologies, 11149 North Torrey Pines Rd., Suite 110, La Jolla, CA, 92037. E-mail: davidlo{at}dgt.com .

Autoimmune diabetes is associated with T helper 1 polarization, but protection from disease can be provided by the application of T helper 2 (Th2) cytokines. To test whether genetic manipulation of T-cells can provide protective Th2 responses, we developed transgenic mice in which T-cells express the interleukin-4—specific transcription factor c-Maf. When crossed with a transgenic model that combines a class II restricted T-cell receptor specific for influenza hemagglutinin with islet ß-cell expression of hemagglutinin, the c-Maf transgene provided significant protection from spontaneous autoimmunity but not from adoptively transferred diabetes. In a second transgenic model in which islet cells express the lymphocytic choriomeningitis virus nucleoprotein, the virus infection triggers autoimmune diabetes within a few weeks involving both CD4 and CD8 T-cells; here too transgenic c-Maf provided significant protection. Surprisingly, when the c-Maf transgene was backcrossed with the NOD model of spontaneous disease, no protection was evident. Thus, transgenic c-Maf can strongly influence autoimmune disease development in some models, but additional factors, such as background genetic differences, can influence the potency of its effect.

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