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Altered Th1 Cell Differentiation Programming by CIITA Deficiency¹

Dipak R. Patel^*, Mark H. Kaplan and Cheong-Hee Chang^2,

^* Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109; Department of Microbiology and Immunology and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202, and Walther Cancer Institute, Indianapolis, IN 46208

CD4 T cell differentiation is a complex process affected by many transcription factors interacting in a tightly regulated manner. We have previously shown that CIITA-deficient mouse Th1 cells expressed Th2-type cytokines, while IFN- expression was normal. In this study, we show that CIITA-deficient Th1 cells contain three distinct populations: cells secreting IL-4 alone, IFN- alone, and both IL-4 and IFN- together. This novel phenotype is stable over multiple rounds of stimulation in the presence of Th1-inducing factors. CIITA-deficient Th1 cells require TCR-mediated signaling to express Th2 cytokines, and this occurs with similar kinetics as wild-type Th2 cells. Both GATA-3 and IL-4 appear to be required for CIITA-deficient Th1 cells to express Th2-type cytokines. Interestingly, however, CIITA-deficient Th1 cells can produce IL-4 in the absence of exogenous IL-4. Introducing either CIITA or antisense GATA-3 during Th1 differentiation partially reduces Th2-type cytokine expression. With the exception of Th2-type cytokine expression, Th1 differentiation occurs normally in the absence of CIITA, as measured by expression of T-bet, IL-12R2, IL-18R, and IFN-. Therefore, CIITA plays a key role to repress Th2-type cytokine expression as naive CD4 T cells differentiate toward the Th1 lineage.

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