MHC class I polypeptide-related sequence A, MHC class I polypeptide-related sequence B, and UL16-binding protein family (MICA/MICB/ULBP)

The MICA/MICB/ULBP family consists of stress-induced cell surface glycoproteins that function as ligands for the NKG2D activating receptor, which is expressed on natural killer (NK) cells, CD8+ T cells, and γδ T cells [Frontiers in Immunology, 2016; NIH, 2025]. This family includes MHC class I polypeptide-related sequence A (MICA), MHC class I polypeptide-related sequence B (MICB), and the UL16-binding proteins (ULBP1-6) [NIH, 2023; R&D Systems, 2002]. These proteins are typically absent or expressed at very low levels in healthy tissues but are significantly upregulated in response to cellular stress, such as DNA damage, viral infection, or oncogenic transformation [Frontiers in Immunology, 2016; NIH, 2021]. The binding of these ligands to NKG2D provides a critical 'danger signal' that triggers the immune system to eliminate the stressed or transformed cells [NIH, 2025; AACR, 2002]. In many cancers, tumor cells evade this immunosurveillance by shedding these ligands from their surface through proteolytic cleavage by metalloproteinases like ADAM10 and ADAM17, creating soluble forms that can block or downregulate NKG2D receptors on immune cells [Taylor & Francis, 2021; Frontiers in Immunology, 2016]. Therapeutic strategies targeting this family include monoclonal antibodies that prevent shedding or promote antibody-dependent cellular cytotoxicity (ADCC), as well as CAR-T cells and bispecific engagers designed to exploit the high expression of these ligands on tumor cells [NIH, 2021; ResearchGate, 2023].

Other names

NKG2D ligandsNKG2DLRAET1 familyStress-induced ligandsMHC class I-related chain A/BMIC family

Antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), inhibition of ligand shedding to restore NKG2D receptor activity, and CAR-T cell-mediated tumor lysis [Frontiers in Immunology, 2016; NIH, 2021; Taylor & Francis, 2021].