Mhc Class Ii Proteins


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 Mhc Class Ii Proteins Background

MHC class II molecules are structurally similar to MHC class I, but have several important differences. The MHC class II molecule on the cell surface is a heterodimer of an alpha and a beta chain encoded by several pairs of genes. In humans these gene pairs are called HLA-DR, -DP, and -DQ. In mice, the two MHC class II molecules are called I-A and I-E.

MHC class II predominantly presents antigens derived from pathogens that are extracellular, although cross-presentation of intracellularly derived peptides can also occur to some extent. The length of peptides bound in the MHC class II molecule is variable. MHC class II gene expression is generally limited to the professional antigen presenting cells (B cells, macrophages, and dendritic cells) and the thymic epithelial cells, although it can be induced in other cell types by interferon-y. In humans, MHC class II is also transiently expressed on activated T cells, although the functional significance of this is unclear.

Assembly of the MHC class II heterodimer begins in the endoplasmic reticulum, where the peptide binding groove is occupied by a transmembrane protein called the invariant chain, which limits the loading of host-derived peptides and helps direct MHC class II to the endocytic pathway. As the MHC - invariant chain complex is exported toward the cell surface, the invariant chain is proteolytically degraded by cathepsins and other proteases, leaving the short invariant chain-derived CLIP peptide in the class II peptide binding groove. In an endosome-like compartment called the MHC class II compartment (MIIC), the MHC class II-like accessory molecule HLA-DM facilitates the exchange of the CLIP peptide with peptides derived from extracellular proteins and pathogens taken up by phagocytosis, receptor-mediated endocytosis, or autophagy. Another class II-like accessory molecule, HLA-DO, regulates HLADM function in a pH-dependent manner in B cells, ensuring that HLA-DM functions in the MIIC only after the endosomal antigens have been processed. The assembled class II - peptide complex is then exported to the cell surface.

The MHC class II - peptide complex is recognized by the T cell receptor of CD4+ T cells. The interaction between antigen presenting cells and the CD4+ T cell can have different outcomes depending on the type of APC and the differentiation state of the T cell. For instance, MHC class II on the surface of thymic epithelium is essential for the positive and negative selection of CD4+ T cells in the thymus. MHC class II on the surface of dendritic cells is important for the initial activation of naive CD4+ T cells. Activated CD4+ T cells can then, in turn, activate B cells or macrophages in a TCR / peptide+MHC class II - dependent interaction.

 

Absence of MHC Class II causes Bare Lymphocyte Syndrome

The MHC class II / T-cell receptor interaction is vital to an effective immune response to many pathogens. The absence of MHC class II gene expression results in a form of severe combined immunodeficiency called the Bare Lymphocyte Syndrome (BLS). BLS is characterized by the near-total absence of a functional CD4+ T cell compartment, due to the inability to positively select CD4+ T cells during development in the thymus. This also results in a defect in humoral immunity, as CD4+ T cell help is required for B cells to undergo proper immunoglobin class switching to produce soluble antibodies and to differentiate into plasma cells.

BLS is a rare autosomal recessive disorder, broken down into four genetic complementation groups, A through D. The defect in BLS patients is not due to a defect in the MHC class II genes themselves, but rather to a defect in one of the four essential transcription factors which are specific to genes in the MHC class II antigen presentation pathway. The defects in BLS complementation groups B, C and D have been mapped to three DNA binding proteins: RFX-ANK, RFX5 and RFX-AP, respectively. Due to cooperative protein binding of these RFX subunits and other DNA binding proteins at the MHC class II promoter, deletion or mutation of any one of these three genes leaves the class II promoter unoccupied by protein and transcriptionally inactive.

 

MHC class II genes are coordinately regulated

Several of the genes of the MHC class II antigen presentation pathway (including the cell surface glycoproteins HLA-DP, -DQ and -DR, the accessory molecules HLADM and HLA-DO, and the invariant chain) are coordinately regulated in their transcription. Each of these genes shares certain conserved elements in the upstream promoter regions, called the "W" or "S," "X," and "Y" boxes. These elements share conserved sequences and spacing, suggesting that they represent the recognition sequences for DNA-binding proteins. Indeed, both the "S" and the "X" boxes have been shown to be occupied by the heterotrimeric RFX complex, made up of RFX5, RFX-AP, and RFX-ANK. The "X" box also contains a CREB binding site. The "Y" box is a CCAAT element, the binding site for the trimeric transcription factor NF-Y that is involved in the expression of many other genes.

The class II transactivator, CIITA, is a non-DNA binding transcription factor which is recruited to the MHC class II promoter through specific protein-protein interactions with RFX, NF-Y and CREB. Upon recruitment to the class II promoter, CIITA in turn recruits the coactivators p300/CBP, PCAF, BRG-1, and several components of the basal transcriptional apparatus to the TATA-less MHC class II promoter, resulting in transcription of the target genes.

CIITA expression is required for the expression of the genes of the MHC class II antigen presentation pathway in most cell types. However, studies of the CIITA knockout mouse have found comparatively low levels of residual CIITA-independent MHC class II expression in some cell types, notably in the thymus, in dendritic cells of the lymph nodes and, to a much lesser extent, germinal center B cells. CIITA has also recently been shown to be involved in the maximal expression of MHC class I genes, particularly in response to IFN-y induction. While the DNAbinding components of the class II transcription complex are constitutively and ubiquitously expressed, the expression of CIITA itself is cell-type specific and tightly regulated. In B cells, macrophages and splenic dendritic cells, CIITA is necessary for MHC class II expression; in most other cell types, ectopic CIITA expression is also sufficient for class II transcription.