Generation of autoreactive CD8 T cell in a mouse model of alopecia areata

Abstract Alopecia areata (AA) is the most frequent form of an organ-specific autoimmune disease in humans mediated by NKG2D +CD8 T cells destroying hair follicles. C3H/HeJ mice naturally develop AA similar to humans, and we found it accompanies the expansion of exhausted phenotype (CD101 +Tim3 +) memory CD8 T cells not only in the skin and skin-draining lymph nodes (SDLNs), but also in the liver and lungs. Before the disease induction, we found these CD8 T cells are activated in the lungs and liver, suggesting they are pre-activated in these organs. In the skin, expanded CD8 T cells additionally upregulated CD39, PD-1, and CTLA-4, which produced less IFNg than those in the SDLN, liver and lungs when stimulated. These features suggest that autoreactive CD8 T cells in the skin are exhausted by chronic antigenic stimulation. However, they did not upregulate TOX, a hallmark of T cell exhaustion. Intriguingly, CD44 highNKG2D-expressing CD8 T cells appeared in the thymi of aged C3H/HeJ mice before disease induction. These cells express TBET and EOMES without overt expansion of PLZF-expressing T cells. Collectively these features suggest AA is mediated by autoreactive activation CD8 T cells that are not explained by previously known mechanisms. This research was supported by the National Research Foundation of Korea (NRF-2022R1A2C1007692)