Class II Transactivator: Mastering the Art of Major Histocompatibility Complex Expression

Major histocompatibility complex (MHC) class II molecules are the predominant presenters of exogenous antigens to T helper cells (reviewed in references 21, 77, and 99). These key molecules are critical for numerous aspects of immune function, including T-cell selection, tolerance induction, antibody production, T-cell-mediated immunity, and the inflammatory response. As principal mediators of transplant rejection, these molecules are often common targets for immune therapies to prevent the rejection of grafted tissues. Class II MHC is implicated as a contributing factor in a host of diseases ranging from rheumatoid arthritis and diabetes to Alzheimer's disease and multiple sclerosis. Constitutive expression of class II MHC is restricted to “professional” antigen-presenting cells but can be induced on various tissues by gamma interferon (IFN-γ). In humans, a congenital lack of both constitutive and inducible class II results in a profound and generally fatal immunodeficiency (type II bare lymphocyte syndrome [BLS]) (7, 29, 45, 61, 67, 75, 112) marked by a significant reduction of CD4+ T cells. Early molecular forays addressing BLS revealed that the genes encoding class II MHC were not defective. Instead, the defect lay in transcription factors controlling class II MHC gene expression. BLS thus became the first disease known to be caused by defective or absent transcription factors. The availability of patient-derived cell lines with class II MHC transcription defects provided a unique tool of nature to identify the requisite transcription factors. Transcriptional regulation of class II MHC expression is complex. Class II MHC and related promoters are characterized by the presence of conserved W (or S), X, and Y boxes (Fig. ​(Fig.1)1) (reviewed in references 10, 67, and 75). The X element is bipartite. The upstream X1 region is recognized by RFX, a trimeric complex of RFX family members including RFX5, RFXANK (RFX-B), and RFXAP (32, 74, 87, 117). The downstream X2 box is bound by X2BP (NF-X2), a complex comprising CREB, and an unidentified 120-kDa protein (83, 84). Another trimeric complex, NF-Y (CBF), which is highly conserved in eukaryotes, binds the Y box (69, 71, 146; reviewed in reference 70). A number of factors interacting with the W box have been described, including the RFX complex (26, 48, 120). The factors involved in X and Y box binding are ubiquitous and expressed constitutively yet fail to account for either constitutive or IFN-γ-inducible class II MHC expression. Somatic cell fusions using BLS patient-derived cells allowed the definition of complementation groups, with each group containing a defect in a single genetic locus. This type of analysis revealed a crucial locus, aIr-1, which in all likelihood encodes the class II transactivator (CIITA), which explained the lack of class II transcription in BLS complementation group A (1, 118). Group A cells express the requisite X and Y binding proteins but fail to transcribe class II. CIITA expression appears to be a nearly absolute requisite for expression of class II MHC, whether constitutive or inducible (17, 19, 23, 47, 85, 103, 114, 118, 119). A number of class II MHC-related genes including genes encoding HLA-DM (H-2M in mice) and invariant chain (Ii), with promoters similar to those for classical class II genes, are also regulated by CIITA (17, 18, 22, 23, 50, 137). CIITA can also upregulate expression of class I MHC genes and beta-2-microglobulin (β2m) through effects at site α in addition to X- and Y-like sequences in the promoters for these genes (40, 72, 104). These initial observations have led to the view that CIITA is a master, or global, regulator for expression of class II MHC and related genes. FIG. 1 Organization of W, X, Y, and other motifs in the promoters of class II MHC and related genes. Genes coding for class II MHC and related proteins contain well conserved W, X, and Y boxes, the presence of which correlates with transcriptional regulation . Since the discovery of CIITA, numerous primary articles and several reviews on its role in regulating the class II MHC have been published. In this review, we will discuss the molecular structure of this novel protein, its mechanism of function, and its biologic and clinical relevance, which is broad.