HGNC Approved Gene Symbol: MICB
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38): 6:31,494,918-31,511,124 (from NCBI)
See MICA (600169). MICA and MICB are divergent image C-related molecules. Their characteristics include the lack of association with beta-2-microglobulin (B2M; 109700), stable expression without conventional class I peptide ligands, and the absence of a CD8 binding site. The 5-prime-end flanking regions of the genes for MICA and MICB include putative heat-shock elements similar to those of heat-shock protein-70 genes (see 140550), and the encoded mRNAs are increased in heat-shock-stressed epithelial cells (Groh et al., 1996).
T cells expressing gamma/delta T-cell receptors (see 186970) recognize antigens without restriction by polymorphic MHC class I or class II molecules and their associated peptide ligands. T cells with variable region V-delta-1 gamma/delta receptors represent 70 to 90% of the gamma/delta T cells in the intestinal epithelium and may function as sentinels that respond to self antigens. Groh et al. (1998) demonstrated that MICA and MICB were recognized by this subset of T cells. These interactions involved the alpha-1/alpha-2 domains of MICA and MICB but were independent of antigen processing. Groh et al. (1998) stated that, with intestinal epithelial cell lines, expression and recognition of MICA and MICB could be stress induced; thus, these molecules may broadly regulate protective responses by the V-delta-1 gamma/delta T cells in the epithelium of the intestinal tract.
The MICA/MICB locus is not conserved in mice; however, mice do have counterpart NKG2D (602893) ligands, Rae1-beta and H60. Diefenbach et al. (2001) demonstrated that ectopic expression of these ligands in tumor cell lines resulted not only in potent rejection mediated by either natural killer (NK) cells or CD8-positive T cells, but that mice subsequently challenged with tumor cell lines not expressing the ligands were also immune to the tumors. Girardi et al. (2001) determined that immunity to cutaneous malignancies could be mediated by NKG2D-expressing intraepithelial gamma/delta T cells. Girardi et al. (2001) proposed that the diverse expression of NKG2D on cytolytic cell types may allow attacks on tumor cells in different anatomical compartments and that gamma/delta T cells may be particularly important in skin and gut.
NK cells and their targets interact through receptors and ligands found in ordered structures, termed immune synapses. Using immunofluorescence and confocal microscopy, Roda-Navarro et al. (2006) found that incubation of a B-cell line stably expressing MICB with NK cells led to bidirectional transfer of NKG2D and MICB at the synapse between the effector and target cells. Subsequently, the NK cells showed reduced cytotoxic capacity when they encountered MICB-expressing target cells.
Stern-Ginossar et al. (2007) developed an algorithm for the prediction of miRNA targets and applied it to human cytomegalovirus miRNAs, resulting in the identification of the MICB gene as a top candidate target of human cytomegalovirus-miR-UL112. MICB is a stress-induced ligand of the NK cell-activating receptor NKG2D and is critical for the NK cell killing of virus-infected cells and tumor cells. Stern-Ginossar et al. (2007) showed that human cytomegalovirus-miR-UL112 specifically downregulates MICB expression during viral infection, leading to decreased binding of NKG2D and reduced killing by NK cells. The authors concluded that their results revealed a miRNA-based immunoevasion mechanism that appears to be exploited by human cytomegalovirus.
Ferrari de Andrade et al. (2018) rationally designed antibodies targeting the MICA alpha-3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA and MICB by human cancer cells. These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and reduced human melanoma metastases in a humanized mouse model. Antitumor immunity was mediated mainly by natural killer cells through activation of NKG2D (611817) and CD16 (see 146740) Fc receptors. Ferrari de Andrade et al. (2018) concluded that their approach prevents the loss of important immunostimulatory ligands by human cancers and reactivates antitumor immunity.
Nalabolu et al. (1996) showed that the MICA and MICB genes occur in a 200-kb region spanning the TNFA (191160) and TNFB (153440) cluster at 6p21.3.
Fischer et al. (2000) described 3 novel MICB alleles, confirming previous findings that most of the polymorphisms in the MICB gene, as in MICA, are coding, and suggested that the extent of polymorphism in the 2 genes may be comparable.
Diefenbach, A., Jensen, E. R., Jamieson, A. M., Raulet, D. H. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 413: 165-171, 2001. [PubMed: 11557981] [Full Text: https://doi.org/10.1038/35093109]
Ferrari de Andrade, L., Tay, R. E., Pan, D., Luoma, A. M., Ito, Y., Badrinath, S., Tsoucas, D., Franz, B., May, K. F., Jr., Harvey, C. J., Kobold, S., Pyrdol, J. W., Yoon, C., Yuan, G.-C., Hodi, F. S., Dranoff, G., Wucherpfennig, K. W. Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity. Science 359: 1537-1542, 2018. [PubMed: 29599246] [Full Text: https://doi.org/10.1126/science.aao0505]
Fischer, G., Perez-Rodriguez, M., Arguello, J. R., Cox, S. T., McWhinnie, A., Travers, P. J., Madrigal, J. A. Three novel MICB alleles. Tissue Antigens 55: 166-170, 2000. [PubMed: 10746790] [Full Text: https://doi.org/10.1034/j.1399-0039.2000.550210.x]
Girardi, M., Oppenheim, D. E., Steele, C. R., Lewis, J. M., Glusac, E., Filler, R., Hobby, P., Sutton, B., Tigelaar, R. E., Hayday, A. C. Regulation of cutaneous malignancy by gamma-delta T cells. Science 294: 605-609, 2001. [PubMed: 11567106] [Full Text: https://doi.org/10.1126/science.1063916]
Groh, V., Bahram, S., Bauer, S., Herman, A., Beauchamp, M., Spies, T. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc. Nat. Acad. Sci. 93: 12445-12450, 1996. [PubMed: 8901601] [Full Text: https://doi.org/10.1073/pnas.93.22.12445]
Groh, V., Steinle, A., Bauer, S., Spies, T. Recognition of stress-induced MHC molecules by intestinal epithelial gamma-delta T cells. Science 279: 1737-1740, 1998. [PubMed: 9497295] [Full Text: https://doi.org/10.1126/science.279.5357.1737]
Nalabolu, S. R., Shukla, H., Nallur, G., Parimoo, S., Weissman, S. M. Genes in a 220-kb region spanning the TNF cluster in human MHC. Genomics 31: 215-222, 1996. [PubMed: 8824804] [Full Text: https://doi.org/10.1006/geno.1996.0034]
Roda-Navarro, P., Vales-Gomez, M., Chisholm, S. E., Reyburn, H. T. Transfer of NKG2D and MICB at the cytotoxic NK cell immune synapse correlates with a reduction in NK cell cytotoxic function. Proc. Nat. Acad. Sci. 103: 11258-11263, 2006. [PubMed: 16849432] [Full Text: https://doi.org/10.1073/pnas.0600721103]
Stern-Ginossar, N., Elefant, N., Zimmermann, A., Wolf, D. G., Saleh, N., Biton, M., Horwitz, E., Prokocimer, Z., Prichard, M., Hahn, G., Goldman-Wohl, D., Greenfield, C., Yagel, S., Hengel, H., Altuvia, Y., Margalit, H., Mandelboim, O. Host immune system gene targeting by a viral miRNA. Science 317: 376-381, 2007. [PubMed: 17641203] [Full Text: https://doi.org/10.1126/science.1140956]