Regulation of MHC class II expression via CIITA protein interactions and phosphorylation.

Abstract

The Major Histocompatibility Complex (MHC) class II is an important family of molecules in the adaptive immune system, responsible for presenting antigenic peptides to the T cell receptor on CD4<super>+</super> T cells in an interaction that provides specificity to the immune response to many pathogens. Proper expression of MHC class II is important in CD4<super> +</super> T cell development, CD4<super>+</super> T cell activation, B cell-mediated humoral immune responses, and macrophage activation. Regulation of MHC class II gene expression in these diverse situations is controlled by the cell-type specific MHC class II transactivator, CIITA. CIITA is a non-DNA binding transcriptional coactivator which coordinates the expression of several genes in the MHC class II antigen-presentation pathway. Previous work had identified at least three different protein isoforms of CIITA, each with independently-regulated expression patterns. However, it had not been determined whether or not these isoforms were functionally equivalent. Here, we describe two levels at which CIITA activity can be regulated. First, we show that the different isoforms of CIITA expressed in different cell types have different transactivation potentials at the MHC class II gene promoters. The isoform expressed in immature dendritic cells and macrophages (DC-CIITA) is a stronger transactivator than the B-CIITA isoform found in dendritic cells, B cells and activated human T cells. The difference in activities is due to the presence of an amino-terminal caspase recruitment domain (CARD) in DC-CIITA which may mediate additional protein-protein interactions for this isoform. Next, we show that CIITA can be post-translationally modified on serines and tyrosines to modulate its transactivation activity. Phosphorylation of CIITA on serines enhanced CIITA activity by increasing its ability to interact with other components of the MHC class II transcriptional complex. In contrast, phosphorylation of CIITA on tyrosine residues by Src family kinases inhibited CIITA transactivation ability by reducing the amount of CIITA protein in the nucleus. Together, the expression of different protein isoforms of CIITA and differential post-translational modifications allows cells of the immune system to regulate the expression of the MHC class II genes in a variety of cell types and situations for an effective adaptive immune response.