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The Role of the MHC Class II Transactivator in Class II Expression and Antigen Presentation by Astrocytes and in Susceptibility to Central Nervous System Autoimmune Disease¹

Olaf Stüve^*, Sawsan Youssef, Anthony J. Slavin, Chelsea L. King^*, Juan Carlos Patarroyo^*, David L. Hirschberg, W. June Brickey^¶, Jeanne M. Soos^||, Janet F. Piskurich^#, Harold A. Chapman and Scott S. Zamvil^2,*

Departments of ^* Neurology and Pulmonary Medicine, University of California, San Francisco, CA 94143; Department of Neurology, Stanford University, Stanford, CA 94305; Tularik, South San Francisco, CA 94080; ^¶ University of North Carolina, Chapel Hill, NC 27599; and ^|| Glaxo SmithKline Pharmaceuticals, King of Prussia, PA 19406; and ^# Mercer University School of Medicine, Macon, GA 31207

The role of the MHC class II transactivator (CIITA) in Ag presentation by astrocytes and susceptibility to experimental autoimmune encephalomyelitis (EAE) was examined using CIITA-deficient mice and newly created transgenic mice that used the glial fibrillary acidic protein promoter to target CIITA expression in astrocytes. CIITA was required for class II expression on astrocytes. Like class II-deficient mice, CIITA-deficient mice were resistant to EAE by immunization with CNS autoantigen, although T cells from immunized CIITA-deficient, but not class II-deficient, mice proliferated and secreted Th1 cytokines. CIITA-deficient splenic APC presented encephalitogenic peptide to purified wild-type encephalitogenic CD4⁺ T cells, indicating that CIITA-independent mechanisms can be used for class II-restricted Ag presentation in lymphoid tissue. CIITA-deficient mice were also resistant to EAE by adoptive transfer of encephalitogenic class II-restricted CD4⁺ Th1 cells, indicating that CIITA-dependent class II expression was required for CNS Ag presentation. Despite constitutive CIITA-driven class II expression on astrocytes in vivo, glial fibrillary acidic protein-CIITA transgenic mice were no more susceptible to EAE than controls. CIITA-transfected astrocytes presented peptide Ag, but in contrast to IFN--activated astrocytes, they could not process and present native Ag. CIITA-transfected astrocytes did not express cathepsin S without IFN- activation, indicating that CIITA does not regulate other elements that may be required for Ag processing by astrocytes. Although our results demonstrate that CIITA-directed class II expression is required for EAE induction, CIITA-directed class II expression by astrocytes does not appear to increase EAE susceptibility. These results do not support the role of astrocytes as APC for class II-restricted Ag presentation during the induction phase of EAE.

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