Genetics, genomics, and evolutionary biology of NKG2D ligands

Abstract

Human and mouse NKG2D ligands (NKG2DLs) are absent or only poorly expressed by most normal cells but are upregulated by cell stress, hence, alerting the immune system in case of malignancy or infection. Although these ligands are numerous and highly variable (at genetic, genomic, structural, and biochemical levels), they all belong to the major histocompatibility complex class I gene superfamily and bind to a single, invariant, receptor: NKG2D. NKG2D (CD314) is an activating receptor expressed on NK cells and subsets of T cells that have a key role in the recognition and lysis of infected and tumor cells. Here, we review the molecular diversity of NKG2DLs, discuss the increasing appreciation of their roles in a variety of medical conditions, and propose several explanations for the evolutionary force(s) that seem to drive the multiplicity and diversity of NKG2DLs while maintaining their interaction with a single invariant receptor.

Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

“…The observed allele frequencies were in line with data obtained from other European and European-American populations for this locus. 18 All relevant covariates for the analyzed clinical outcomes were equally distributed in the MICA-matched and MICA-mismatched patients, with the exception of patients' age category at the time of transplant, which reflects the fact that older patients (age . 49 years) were slightly (P 5 .02) better matched for MICA (Table 1).…”

“…It encodes a single-chain (b 2 -microglobulinindependent), cargo (peptide)-free cell surface glycoprotein that is upregulated by cell stress. 18 The MICA gene was discovered by the senior author (S.B.) 20 years ago and is located within the MHC, 46 kb centromeric to the HLA-B locus.…”

“…MICA binds NKG2D, an activating receptor expressed on the surface of cytotoxic CD8 1 ab and gd T lymphocytes, as well as natural killer (NK) cells. 18 Within the intestinal epithelium, MICA is also recognized by the T-cell receptor of Vd1-bearing gd T cells. 20 Previous studies have hinted at a role for MICA in GVHD, but these analyzed MICA diversity only in patients (not donors) and/or in small, single-center cohorts, which engendered controversial, if not opposite, conclusions.…”

Mechanisms of Acute Toxicity in NKG2D Chimeric Antigen Receptor T Cell–Treated Mice

“…This activation of host myeloid and lymphoid cells is involved in NKG2D CAR T cell efficacy (22–24). Human NKG2D recognizes MICA, and MICB, ULBP1 - 6 on human cells, while murine NKG2D binds to Rae1 proteins, H60 proteins, and MULT1 in mice (25). These ligands are thought to be expressed on the cell surface in low amounts and on few tissues and not at all on most healthy tissues, although they can be induced by acute infection, irradiation, and chemotherapeutic agents through mechanisms involving the ATM/ATR DNA repair pathways (19, 26–30).…”

Impact of the MICA-129Met/Val Dimorphism on NKG2D-Mediated Biological Functions and Disease Risks

“…Since the MICA-129 dimorphism is considered as decisive for distinguishing low- and high-affinity variants (22), the frequency of alleles encoding high-affinity MICA variants is expected to match the frequency of the MICA-129Met variant. However, other MICA polymorphisms and their interaction need to be studied further (73). …”