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.
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.
Itoh-Lindstrom
Y
Y
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill 27599, USA.
Piskurich
J F
JF
Felix
N J
NJ
Wang
Y
Y
Brickey
W J
WJ
Platt
J L
JL
Koller
B H
BH
Ting
J P
JP
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D003433:Crosses, Genetic; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D018390:Gene Targeting; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000235:genetics; D017099:IgG Deficiency / Q000235:genetics; D007075:Immunoglobulin M / Q000097:blood; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins; D010446:Peptide Fragments / Q000172:deficiency / Q000235:genetics*; D017384:Sequence Deletion; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics*; D015854:Up-Regulation / Q000276:immunology
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D010446:Peptide Fragments; D015534:Trans-Activators; C045084:invariant chain; D015847:Interleukin-4; D007371:Interferon-gamma; D019204:GTP-Binding Proteins