MHC class II

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Schematic representation of MHC class II.

MHC (major histocompatibility complex) class II molecules are a family of molecules normally found only on antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, and B cells.

The antigens presented by class II peptides are derived from extracellular proteins (not cytosolic as in class I); hence, the MHC class II-dependent pathway of antigen presentation is called the endocytic or exogenous pathway.

Loading of a MHC class II molecule occurs by phagocytosis; extracellular proteins are endocytosed, digested in lysosomes, and the resulting epitopic peptide fragments are loaded onto MHC class II molecules prior to their migration to the cell surface.

Structure[edit]

Like MHC class I molecules, class II molecules are also heterodimers, but in this case consist of two homogenous peptides, an α and β chain, both of which are encoded in the MHC.[1] The subdesignation α1, α2, etc. refers to separate domains within the HLA gene; each domain is usually encoded by a different exon within the gene, and some genes have further domains that encode leader sequences, transmembrane sequences, etc.

Because the antigen-binding groove of MHC class II molecules is open at both ends while the corresponding groove on class I molecules is closed at each end, the antigens presented by MHC class II molecules are longer, generally between 15 and 24 amino acid residues long.

Expression[edit]

These molecules are constitutively expressed in professional, immune antigen presenting cells, but may also be induced on other cells by interferon γ.[2]

MHC class II is also expressed on group 3 innate lymphoid cells.

Reaction to bacteria[edit]

Because class II MHC is loaded with extracellular proteins, it is mainly concerned with presentation of extracellular pathogens (for example, bacteria that might be infecting a wound or the blood). Class II molecules interact mainly with immune cells, like the T helper cell (TCD4+) . The helper T cells then help to trigger an appropriate immune response which may include localized inflammation and swelling due to recruitment of phagocytes or may lead to a full-force antibody immune response due to activation of B cells.

Synthesis[edit]

During synthesis of class II MHC in the endoplasmic reticulum, the α and β chains are produced and complexed with a special polypeptide known as the invariant chain. The nascent MHC class II protein in the rough ER has its peptide-binding cleft blocked by the invariant chain (Ii; a trimer) to prevent it from binding cellular peptides or peptides from the endogenous pathway (such as those that would be loaded onto class I MHC).

The invariant chain also facilitates the export of class II MHC from the ER to the golgi, followed by fusion with a late endosome containing endocytosed, degraded proteins. The invariant chain is then broken down in stages by proteases called cathepsins, leaving only a small fragment known as CLIP which maintains blockage of the peptide binding cleft on the MHC molecule. An MHC class II-like structure, HLA-DM, facilitates CLIP removal and allows the binding of peptides with higher affinities. The stable class II MHC is then presented on the cell surface.

Genes[edit]

Alpha Beta
HLA-DM HLA-DMA HLA-DMB
HLA-DO HLA-DOA HLA-DOB
HLA-DP HLA-DPA1 HLA-DPB1
HLA-DQ HLA-DQA1, HLA-DQA2 HLA-DQB1, HLA-DQB2
HLA-DR HLA-DRA HLA-DRB1, HLA-DRB3, HLA-DRB4, HLA-DRB5

Pathways controlling MHC class II antigen presentation[edit]

Pathway: PSD4 - ARL14/ARF7 - MYO1E[edit]

Molecules involved[edit]

Several molecules are involved in this pathway.[3]

- PIK3R2[4] and PIP5K1A[5] are two kinases that create substrates for PSD4.

- PSD4[6][7] (Pleckstrin and Sec7 Domain containing 4) is a GEF (Guanine Exchange Factor) that loads ARL14/ARF7 with GTP.

- ARL14/ARF7[8] is a Small GTPase protein that is selectively expressed in immune cells. This protein is localized within MCH-II compartments in immature Dendritic Cells.

- ARF7EP[9] is an effector of ARL14/ARF7 that interacts with MYO1E.

- MYO1E[10] is a protein that controls MHC-II compartments with an actin-based mechanism.

Pathway[edit]

PIK3R2 and PIP5K1A are two Kinases that phosphorylates Phosphatidylinositol (PIP) providing PSD4 with substrates for its GTP loading ability. PSD4 as a Guanine Exchange Factor, loads ARL14/ARF7 with GTP. Subsequently, ARF7EP interacts with MYO1E which binds itself to Actin myofibers. Altogether, this complex contributes to maintain MHC-II loaded vesicles within the Immature Dendritic Cell, impeding its translocation to Cell Membrane.

Picture showing PSD4 - ARL14/ARF7 - MYO1E Pathway.
Pathway showing how MHC-II distribution is controlled within Immature Dendritic Cells.

See also[edit]

Cross-presentation

References[edit]

  1. ^ "Histocompatibility". Retrieved 2009-01-21. 
  2. ^ "Genetic control of MHC class II expression.". Cell. 109 Suppl: S21–33. Apr 2002. doi:10.1016/s0092-8674(02)00696-7. PMID 11983150. 
  3. ^ A Genome-wide multidimensional RNAi screen reveals pathways controlling MHC class II antigen presentation. Cell. 2011 Apr 15;145(2):268-83. doi: 10.1016/j.cell.2011.03.023. Epub 2011 Mar 31.
  4. ^ PIK3R2 phosphoinositide-3-kinase, regulatory subunit 2 (beta) [Homo sapiens (human)] - Gene - NCBI
  5. ^ PIP5K1A phosphatidylinositol-4-phosphate 5-kinase, type I, alpha [Homo sapiens (human)] - Gene - NCBI
  6. ^ PSD4 pleckstrin and Sec7 domain containing 4 [Homo sapiens (human)] - Gene - NCBI
  7. ^ ARF6 controls post-endocytic recycling through its downstream exocyst complex effector. J Cell Biol. 2003 Dec 8;163(5):1111-21.
  8. ^ ARL14 ADP-ribosylation factor-like 14 [Homo sapiens (human)] - Gene - NCBI
  9. ^ ARL14EP ADP-ribosylation factor-like 14 effector protein [Homo sapiens (human)] - Gene - NCBI
  10. ^ MYO1E myosin IE [Homo sapiens (human)] - Gene - NCBI

External links[edit]