How are class II MHC genes turned on and off?

Abstract

Fragments of foreign antigen are detected by CD4+ helper T cells via the T cell receptor for antigen in the context of major histocompatibility complex (MHC) class II molecules. Very few cells normally express class II MHC molecules, and these cells play critical roles in antigen presentation and in the thymic selection of T lymphocytes before their exit into the periphery. Because of the central role the class II MHC molecules play in immune system function, it is not surprising that the lack of expression of these molecules results in a severe combined immunodeficiency disorder (called bare lymphocyte syndrome) and that the aberrant expression of the molecules is frequently observed in the target organs of various autoimmune disorders (e.g., multiple sclerosis and rheumatoid arthritis). Because both classes of disease could conceivably be treated by molecular approaches targeted at either restoring or inhibiting expression of class II MHC genes, there has been an intense effort during the past decade to elucidate the regulatory mechanisms of class II MHC genes. An analysis of recent advances in this effort is provided in this review article.

Repression of MHC class II gene transcription in trophoblast cells by novel single-stranded DNA binding proteins

“…The expression of MHC class II genes in trophoblasts may therefore be the result of a balance between the activity of IAαNRE and coactivators such as CIITA. Other possibilities include interactions with histones or factors such as HMG that bend DNA (Abdulkadir and Ono, 1995;Kingston et al, 1996). Genomic footprinting of the stable R8RP.3 clones containing integrated copies of the IAα pro CAT genes will help address these alternatives.…”

“…The proximal promoters of all class II genes contain several highly conserved cis-acting sequences that are required for both constitutive and IFN-γ inducible transcription in B cells and other cell types (reviewed in Benoist and Mathis, 1990;Glimcher and Kara, 1992). The function of these cis-acting sequences, termed the W (also named H, S or Z), X and Y boxes, is mediated by the binding of transacting factors (Glimcher and Kara, 1992;Abdulkadir and Ono, 1995). Positive regulatory sequences have also been defined in the distal promoters of class II genes; these include the B cell response elements (BRE-1 and BRE-2; Boothby et al, 1988) and the lipopolysaccharide element (LRE; Gravellese et al, 1989).…”

Complex Architecture of Major Histocompatibility Complex Class II Promoters: Reiterated Motifs and Conserved Protein-Protein Interactions

“…The end result of these interactions is to activate and differentiate antigen-specific B cells to plasma cells (2). Expression of class II is carefully regulated at the level of transcription such that high levels of these proteins are observed on the surface of B cells, activated human T cells, and many somatic and antigen-presenting cells after their induction by the T-cell lymphokine gamma interferon (IFN-␥) (1,4,8,13,24).Since the DRA gene is invariant and is expressed at the highest levels of all class II genes, its promoter has been studied extensively (1,8,24). Lessons learned with the DRA promoter hold for other class II promoters (1,4,8,13,24,48).…”

“…NF-Y binds to the Y box (45) and members of the Oct family of transcription factors bind to the octamer-binding site (34,39,47). However, proteins that bind to the S box have not been identified (1,4,6,7,13,24).The S box, which was named for Servenius (32) and is also known as the heptamer, septamer, W, H, or Z box, contains seven nucleotides (GGACCCT) (6,7,13,44). Some of the confusion caused by these other names is due to their inclusion of its 5Ј-flanking sequence, which is required for the function of the S box (44).…”

“…The end result of these interactions is to activate and differentiate antigen-specific B cells to plasma cells (2). Expression of class II is carefully regulated at the level of transcription such that high levels of these proteins are observed on the surface of B cells, activated human T cells, and many somatic and antigen-presenting cells after their induction by the T-cell lymphokine gamma interferon (IFN-␥) (1,4,8,13,24).…”