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International Immunology, Vol. 13, No. 7, 951-958, July 2001
© 2001 Japanese Society for Immunology

Combinations of dominant-negative class II transactivator, p300 or CDK9 proteins block the expression of MHC II genes

Satoshi Kanazawa and B. Matija Peterlin Departments of Medicine, Microbiology and Immunology, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143-0703, USA

Correspondence to: B. M. Peterlin

The class II transactivator (CIITA) regulates not only the transcription of HLA-DR, -DQ, -DP, but also invariant chain, DMA and DMB genes. A hybrid mutant CIITA protein, which contained residues from positions 302 to 1130 in CIITA fused to the enhanced green fluorescent protein (EdCIITA), inhibited the function of the wild-type protein. EdCIITA extinguished the inducible and constitutive expression of MHC II genes in epithelial cells treated with IFN-{gamma} and B lymphoblastoid cells respectively. Also, it blocked T cell activation by superantigen. This inhibition correlated with the localization of EdCIITA but not CIITA in the cytoplasm of cells. However, when EdCIITA was co-expressed with a dominant-negative form of the nucleoporin Nup214/CAN, it also accumulated in the nucleus. These data suggest that EdCIITA not only competes with the wild-type protein for the binding to MHC II promoters but sequesters a critical co-factor of CIITA in the cytoplasm. CIITA also recruits the histone acetyltransferase cAMP responsive element binding protein (CREB) binding protein and positive transcription elongation factor b (p-TEFb) for the transcription of MHC II genes. Dominant-negative p300 (DNp300) or CDK9 (DNCDK9) proteins inhibited the function of CIITA and of the DRA promoter. Thus, combinations of EdCIITA and DNp300 and/or DNCDK9 proteins extinguished the transcription of MHC II genes. They might become useful for future genetic therapeutic approaches in organ transplantation and autoimmune diseases.

Keywords: class II transactivator, CREB binding protein, dominant-negative protein, enhanced green fluorescent protein, MHC II, positive transcription elongation factor b

Transmitting editor: T. Sasazuki


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