Deregulated MHC Class II Transactivator Expression Leads to a Strong Th2 Bias in CD4+ T Lymphocytes

Abstract

The MHC class II (MHC-II) transactivator (CIITA) is the master transcriptional regulator of genes involved in MHC-II-restricted Ag presentation. Fine tuning of CIITA gene expression determines the cell type-specific expression of MHC-II genes. This regulation is achieved by the selective usage of multiple CIITA promoters. It has recently been suggested that CIITA also contributes to Th cell differentiation by suppressing IL-4 expression in Th1 cells. In this study, we show that endogenous CIITA is expressed at low levels in activated mouse T cells. Importantly CIITA is not regulated differentially in murine and human Th1 and Th2 cells. Ectopic expression of a CIITA transgene in multiple mouse cell types including T cells, does not interfere with normal development of CD4+ T cells. However, upon TCR activation the CIITA transgenic CD4+ T cells preferentially differentiate into IL-4-secreting Th2-type cells. These results imply that CIITA is not a direct Th1-specific repressor of the IL-4 gene and that tight control over the expression of CIITA and MHC-II is required to maintain the normal balance between Th1 and Th2 responses.

Revisiting the specificity of the MHC class II transactivator CIITA in vivo

“…In contrast, Tg-CIITA mRNA abundance increased during the activation of CD4 + T cells, reaching levels higher than those found in control B cells (Fig. 2B) [15]. This enhanced CIITA expression augments the expression of MHC-II and related genes to levels close to those found in B cells.…”

“…2B). In non-Tg cells, CIITA mRNA levels did not increase upon activation [15]. In contrast, Tg-CIITA mRNA abundance increased during the activation of CD4 + T cells, reaching levels higher than those found in control B cells (Fig.…”

“…Third, experimental support for the new targets is largely limited to a correlation between their expression and that of CIITA, altered expression in CIITA-deficient cells and/or experiments involving transfections and reporter gene assays [4]. Finally, certain targets have been the subject of controversy [15][16][17][18].…”

“…Deregulated cytokine expression in CIITA-Tg CD4 + T cells CIITA has been shown to modulate expression of the genes encoding IL-4 and IFN-c in activated mouse Th cells [8,15,16,18]. However, this influence of CIITA on cytokine production and the mechanisms that are responsible have been a matter of debate [8,15,16,18,[21][22][23].…”

“…However, this influence of CIITA on cytokine production and the mechanisms that are responsible have been a matter of debate [8,15,16,18,[21][22][23]. We therefore addressed this question further using our Tg mice.…”