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 ex
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 ex
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 ex
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.