Research Article

An NKG2D-Mediated Human Lymphoid Stress-Surveillance Response with High Interindividual Variation

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Science Translational Medicine  30 Nov 2011:
DOI: 10.1126/scitranslmed.3002922


DNA damage or other physic-chemico stresses may increase the expression of major histocompatibility complex (MHC) class I-related stress antigens, which then activate lymphocytes. This lymphoid stress-surveillance (LSS) can limit tumor formation, but may also promote immunopathology. MICA is a highly polymorphic human stress-antigen implicated in tumor-surveillance, inflammation, and transplant rejection. However, LSS has not been conclusively demonstrated in humans, and the functional role for MICA polymorphisms remains to be established. Here we show that MICA coding-sequence polymorphisms substantially affected RNA and protein expression. All donors tested showed LSS responses of γδ T and NK cells, but unexpectedly each was individually “tuned”. Hence, some responded optimally to highly-expressed alleles, whereas others responded better to lower MICA expression, challenging the orthodoxy that higher stress-antigen levels promote greater responsiveness. These individual variations in LSS tuning may help explain patient-specific differences in tumor immune-surveillance, transplant rejection, and inflammation as well as provide insight into immune evasion and immune-suppression.