The MHC class II transactivator: A negative regulator of IL-4 and Fas ligand.

Abstract

The major histocompatibility complex class II transactivator (CIITA) is the master regulator of MHC class II genes and other genes involved in the antigen presentation pathway. In the absence of CIITA, MHC class II is not expressed on professional antigen presenting cells (APCs). However, it was not known if CIITA regulates other immune processes. To address this, we investigated whether CIITA plays a role in CD4 T cell function. CD4 T cells can differentiate into two functionally distinct lineages, T helper type 1 (Th1) and Th2. Th1 and Th2 cells are responsible for cell-mediated and humoral immunity, respectively. We found that CIITA is expressed during the Th1 differentiation process, which is required for the inhibition of Th2 cytokines. CIITA deficiency caused developing Th1 cells to produce Th2 cytokines, IL-4, IL-5, and IL-13 in addition to Th1 cytokine IFN-gamma. On the other hand, the constitutive expression of CIITA in the Th2 clone resulted in inhibition of IL-4 production. The inhibitory function of CIITA is due to its ability to interact with other transcription factors. CIITA repressed transcription from the IL-4 promoter by interfering with the interaction of the transcription factor nuclear factor of activated T cells (NF-AT) with the coactivator p300. CIITA also inhibits transcription of the Fas ligand gene whose expression is dependent on NF-AT. The Fas:Fas ligand pathway is critical in regulating immune homeostasis by eliminating activated T cells that have proliferated in response to an infection. CD4 T cells expressing CIITA were resistant to cell death due to the lower level of Fas ligand expression. CIITA deficient CD4 T cells had enhanced levels of Fas ligand on the cell surface during the Th1 differentiation process but not after reactivation. B cells without CIITA also expressed an increased level of Fas ligand. Our data show that CIITA plays an important role by regulating multiple immune responses including antigen presentation, the Th1 differentiation process, and lymphocyte homeostasis.