Stress-induced ligands and altered Major Histocompatibility Complex class I (SIL/MHC-I)

Tumor and infected cells expressing stress ligands and altered MHC class I describes a cellular phenotype characterized by the upregulation of stress-induced proteins and the downregulation of self-recognition markers [PubMed 21775012]. Stress ligands, such as MICA, MICB, and UL16-binding proteins (ULBPs), are typically expressed on the cell surface in response to DNA damage, oncogenic transformation, or viral infection [UniProt Q29983]. These ligands are recognized by the activating receptor NKG2D, primarily found on Natural Killer (NK) cells and CD8+ T cells, triggering an immune-mediated attack [PubMed 30305468]. Simultaneously, many tumors and viruses downregulate Major Histocompatibility Complex (MHC) class I molecules to evade detection by the T-cell receptor (TCR) of cytotoxic T cells, a phenomenon known as missing-self [NIH]. This dual mechanism of immune evasion and stress signaling makes these cells a primary target for advanced immunotherapies, including CAR-T and CAR-NK cells engineered with NKG2D-based chimeric antigen receptors [PubMed 31110104]. Therapeutic challenges include the shedding of stress ligands into the systemic circulation, which can act as decoys to inhibit immune cell activation, and the potential for on-target off-tumor toxicity if ligands are expressed at low levels on healthy tissues [PubMed 28213372].

Other names

NKG2D ligandsMICA/BULBPsMissing-self phenotypeStress-induced cell surface molecules

Engagement of the NKG2D receptor to trigger cytotoxic degranulation and cytokine production against cells expressing MICA/B or ULBPs; restoration of MHC-I expression to facilitate CD8+ T-cell mediated lysis.