Cellular MHC class I proteins

Major histocompatibility complex (MHC) proteins are essential components of the immune system (1). One speeific role is for them to bind and present cellularly derived peptides (-8-10 amino acids - MHC Class I peptides) at the cell surface. These peptides are subsequently challenged by cytolytic T-lymphocytes (CTL s) which are programmed to differentiate between self and exogenous peptides. T-cell recognition of these latter peptides initiates a response that ultimately results in cell lysis and death of the infected cell. Hence, structural characterization of such peptides could potentially result in the development of therapeutie treatments of a number of infectious disease states such as viral cancers, AIDS, and autoimmune disease. However, the task of sequencing such peptides is difficult since MHC class I proteins can bind and present 10,000-15,000 different cellularly derived peptides present at the sub-pieo-femtomole level (2,3). 

Unlike the widely and constitutively expressed classical and non-classical MHC class I proteins, MIG-A and MIG-B are induced only in response to cellular stress on intestinal epithelium, epithelially-derived tumors and vascular endothelium (Groh et al, 1996, 1999). While MIC-A and MIC-B are quite similar to each other ( 84% identical Fig. 5) (Bahram and Spies, 1996 Bahram et al, 1996), they have diverged significantly from the MHC class I family as a whole, with identities of approximately 28% to 35% domain-by-domain when aligned with the human MHC class I proteins. MIC-A and -B are highly polymorphic, with over fifty MIG-A and thirteen... 

Homologues of MHC class 1 proteins have been identified in the genomes of human, murine and rat cytomegaloviruses (CMVs). Given the pivotal role of the MHC class I protein in cellular immunity, it has been postulated that the viral homologues subvert the normal antiviral immune response of the host, thus promoting virus replication and dissemination in an otherwise hostile environment. This review focuses on recent studies of the CMV MHC class I homologues at the molecular, cellular and whole animal level and presents current hypotheses for their roles in the CMV life cycle. 

The response to viral infection involves cellular and cytokine components of the host innate and adaptive immune system. However, viruses have developed protean means of subverting the host immune response. This has been an explosive area of research that has revealed striking examples of the diverse strategies CMV has evolved to counteract host immunity. The MHC is the ultimate interface between virus and adaptive immunity. CDS" and CD4 T lymphocytes recognize peptides derived from viral proteins presented in the context of MHC class I and class II molecules, respectively (Doherty 1995). This recognition triggers the cell-mediated immune system armamentarium whereby virus-specific T lymphocyte clones proliferate and mediate cytolysis of virally infected cells and/or release cytokines that inhibit viral replication or recruit T cells and monocytes to amplify the antiviral response. 

Gene expression experiments revealed that HCMV blocks IFN-ot-stimulated ISGF3-dependent (MHC class I, 2, 5 -OAS, and MxA) and ISGF3-independent (IRF-1) gene expression in infected fibroblasts and ECs (Miller et al. 1999). EMSA analyses, utilizing a DNA-binding element that binds STAT-1 homodimers and STAT-1/STAT-2 heterodimers, revealed that IFN-ot-stimulated transcription factor activation was blocked in HCMV-infected cells (Miller et al. 1999). Immunoprecipitation experiments demonstrated that IFN-ot-stimulated tyrosine phosphorylation was also blocked in HCMV-infected cells, a cellular phenotype that correlates with decreased JAKl protein (Miller et al. 1999). Thus the HCMV-mediated decrease of JAKl protein may mediate disruption of IFN-ot-stimulated responses in a manner analogous to the defect in the IFN-y pathway. 

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