Single-cell profiling identifies a CD8bright CD244bright Natural Killer cell subset that reflects disease activity in HLA-A29-positive birdshot chorioretinopathy.

Abstract MHC-I-opathies are inflammatory conditions strongly associated with HLA class I genes. The striking association with HLA class I suggests involvement of T cells, whereas natural killer (NK) cell involvement remains largely unstudied. Here we show that HLA-A29-positive birdshot chorioretinopathy patients have a skewed NK cell pool containing expanded CD16-positive NK cells which produce more proinflammatory cytokines. These NK cells contain populations that express the HLA class I restricted antigen CD8A which display gene signatures indicative of high cytotoxic activity (IGFBP7, MYOM2, and LINC00996), and signaling through NK cell receptor CD244 (SH2D2A and SH2D1B). Long-term monitoring of a cohort of birdshot chorioretinopathy patients with active disease identified a population of CD8bright CD244bright NK cells, which rapidly declined to normal levels upon clinical remission following successful treatment. Collectively, these studies implicate CD8bright CD244bright NK cells in the sight-threatening MHC-I-opathy, birdshot chorioretinopathy.