Nature immunology · 2026
HLA class I signal peptide variation predicts strength of NKG2A+ NK cell response to missing-self and risk of human disease.
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Lin Zhansong, Bashirova Arman A, Callahan Cian, Nelson George W, Robinson Emma, Viard Mathias, Tang Minzhong, Hildesheim Allan, Franke Andre, Rioux John D, Garcia-Beltran Wilfredo, Carrington Mary
Аннотация
Natural killer (NK) cells expressing inhibitory receptors that recognize self human leukocyte antigen (HLA) class I molecules gain enhanced functionality-a process influenced by genetic polymorphism that dictates the strength of interactions between inhibitory receptors and their HLA ligands. Inhibitory CD94/NKG2A binds HLA-E loaded with epitopes derived from polymorphic HLA class I signal peptides (SPs). We generated a metric, called SP score, that quantifies the overall strength of CD94/NKG2A-HLA-E interactions based on a person's SP genotype. SP scores correlated positively with NKG2A+CD56bright NK cell response to HLA class I-negative cells, indicating that CD94/NKG2A-HLA-E interaction strength promotes NK cell education. Concordantly, higher SP scores associated with lower risk of nasopharyngeal carcinoma and ulcerative colitis. Thus, the SP score may serve as a genetic tool to guide clinical NK cell intervention strategies, including therapeutic NKG2A blockade.