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Regulatory Allospecific NK Cell Function Is Differentially Associated with HLA C Allotypes

Major histocompatibility complex I (MHC I) molecules ‘silence’ natural killer (NK) cell activity. Conversely, NK cell activity is triggered through cells lacking expression of autologous MHC I. Unexpectedly we found that a subset of NK cells is activated rather than silenced when interacting with cells expressing normal levels of autologous MHC I. Instead of inducing an inflammatory phenotype, however, activation led to the secretion of the regulatory cytokines TGF‐β and IL‐10. Importantly, in vitro models of allogeneic interactions showed that targets co‐expressing HLA C1 and C2 epitopes best supported, or even enhanced, this cell‐contact‐mediated regulatory NK cell function. Together, these data ascribe a novel pattern of reactivity to NK cells, with potential implications both in autologous and allogeneic systems.