Reduced IL-4-, lipopolysaccharide-, and IFN-gamma-induced MHC class II expression in mice lacking class II transactivator due to targeted deletion of the GTP-binding domain

Abstract

Class II transactivator (CIITA) is an unusual transcriptional coactivator in that it contains a functionally important, GTP-binding consensus domain. To assess the functional role of the GTP-binding domain of CIITA in vivo, we have generated knockout mice that bear a mutation in the CIITA gene spanning the GTP-binding domain. Upon analysis, these mice show no detectable CIITA mRNA; hence, they represent mice with deleted CIITA rather than mice with defects in the GTP-binding domain only. In these knockout mice, MHC class II expression is nearly eliminated, although a faint RT-PCR signal is visible in spleen, lymph node, and thymus, suggestive of the presence of CIITA-independent regulation of MHC class II expression. Invariant chain expression is also greatly reduced, but to a lesser extent than MHC class II. Serum IgM is not decreased, but the serum IgG level is greatly reduced, further confirming the absence of MHC class II Ag-dependent Ig class switching. Induction of MHC class II expression by IL-4 or LPS was absent on B cells, and Mac-1+ cells showed no detectable induction of MHC class II by either IL-4, LPS, or IFN-gamma. These findings demonstrate a requirement for CIITA in IFN-gamma-, IL-4-, and endotoxin-induced MHC class II expression as well as the possibility of rare CIITA-independent MHC class II expression.