Targeting the NKG2A Pathway in Alopecia Areata

SUMMARY Alopecia Areata (AA) is a chronic autoimmune disease of the hair follicle that results in hair loss. The exact cause of AA is unknown, genetic predisposition and environmental triggers might play important roles in the disease. We previously identified CD8+NKG2D+ T cells as the key pathogenic drivers in AA and our findings led to targeting pathogenic CD8+ T cells through blocking the gamma chain signaling pathway with JAK inhibitors in AA treatment. Recently, we performed single-cell RNA sequencing (scRNAseq) together with single-cell TCR sequencing (scTCRseq), and found that the most highly clonally expanded CD8+NKG2D+ T cells were also positive for the inhibitory receptor, NKG2A. NKG2D is a critical activating receptor in both innate and adaptive immune responses.. In contrast, the inhibitory receptor NKG2A, along with its co-receptor, CD94, engages the nonclassical MHC class I molecule HLA-E in humans, or the Qa-1 molecule in mice. Engagement of NKG2A results in the attenuation of the effector activity of CD8+ T cells. Our discovery of clonally expanded NKG2A+NKG2D+CD8+ T cells is profoundly significant in AA, since it provides a crucial new insight into the nature of the dysregulated effector responses in AA. We postulate that the inhibitory signal from NKG2A/CD94 is not sufficient to attenuate the ongoing immune response AA, and/or that the activating signals such as from NKG2D are too potent to be suppressed by NKG2A signaling. The work outlined in this proposal will interrogate the role of NKG2A in AA pathogenesis, the regulation of ligand expression in the hair follicle, and targeting NKG2A to enhance inhibitory signaling and/or dampen the effector activity of NKG2A+NKG2D+CD8+ T cells as a potential therapeutic strategy for disease. These studies will expand our knowledge of therapeutically enhancing signaling by inhibitory receptors, such as NKG2A, in the setting of autoimmunity, where there is a clear knowledge gap. Our results will have broad relevance to autoimmune diseases that share common genetic causes, common therapeutic targets, and potentially common treatments with AA. .