MHC-Class I-related Chain AB (MICAB)

Major histocompatibility complex class I-related chain A/chain B (MICA/MICB) is highly polymorphic ligands induced by stress, which is expressed at the transcriptional level in all tissues except the central nervous system.

Introduction of MICA/B

The major histocompatibility complex (MHC) class I chain-associated protein A (MICA) and protein B (MICB) are polymorphic proteins that are induced when cells are stressed, destroyed, or transformed. MICA/MICB is a highly divergent and polymorphic human leukocyte antigen (HLA) class I related gene, which is known to be a signal molecule/ligand to signal cell distress. Together with the UL16 binding proteins (ULBPs) family of six proteins, they form part of eight surface glycoproteins. Unlike the classical HLA molecules, they do not participate in antigen presentation, do not bind to β2 microglobulin, do not bind to peptides, and do not express on normal circulating lymphocytes. In the stress response, MIC protein is expressed on the surface of newly isolated gastric epithelial cells, endothelial cells, and fibroblasts, and binds to the activated natural killer cell receptor NKG2D, which is found in many cells of the immune system.

Fig.1 NKG2D-Ligand families. (López-Cobo, 2016)

Function of MICA/B Recognition by γδ T Cells

MICA/B is rarely expressed in normal cells but is often expressed in epithelial tumor cells and stress cells. These stressed cells include those that have undergone heat shock, viral infection, and DNA damage. The immune receptor NKG2D that recognizes MICA/B is expressed by γδ T and NK cells. Therefore, the NKG2D-dependent cytotoxicity may be enhanced with the increase of MICA/B expression.

In addition to its expression under physiological/stress conditions, its expression in viral infections and tumor cells has also been widely reported.

• Cancer

γδ T cells can recognize MICA/MICB in a wide range, including but not limited to lung cancer and oral cancer. This induction may be regulated by the tumor microenvironment, affecting the steady-state conditions that are conducive to tumor growth. NKG2D ligand is usually expressed in multiple parts of tumor epithelium. The lesions include breast, ovary, lung, colon, kidney, pancreas, glioma, and melanoma.

Fig.2 Putative roles of resident and circulating γδ T cells in anticancer surveillance. (Marina, 2002)

• Viral Infections

Respiratory virus infection, especially rhinoviruses (RVs) infection, is the main cause of morbidity and mortality, and the most common cause of exacerbation of asthma. Respiratory viruses mainly enter and replicate respiratory epithelial cells, and epithelial cells play a key role in initiating and regulating the immune response to infection. MICA and B molecules have been reported to be upregulated on stressed and/or rapidly proliferating cells (including pathogen-infected cells). Surface MICA/MICB molecules bind to NKG2D, which leads to the activation of NK and CD8 T cells. Therefore, it may play an important role in promoting the immune response of virus infection.

References

1. López-Cobo, S.,et al. Glycosyl-Phosphatidyl-Inositol (GPI)-Anchors and Metalloproteases: Their Roles in the Regulation of Exosome Composition and NKG2D-Mediated Immune Recognition. Frontiers in Cell and Developmental Biology. 2016, 4.
2. Marina, F., et al. Human γδ T cells: a nonredundant system in the immune-surveillance against cancer. TRENDS in Immunology. 2002, 23(1): 14-18.