IL-27 promotes pathogenic Tfh-like CD4 effectors and exhausted-like CD8 T cells in a mouse model of Sjögren’s

Abstract

Abstract Sjögren’s is an autoimmune disease that targets the exocrine glands leading to profound dryness, extra glandular manifestations, and increased risk of developing lymphoma with no therapy to treat the underlying immune dysregulation. Nonobese diabetic (NOD) mice spontaneously develop T cell mediated inflammation of the lacrimal gland, similar to human disease. IL-27 is elevated in the salvia and serum of people with Sjögren’s and is required for lacrimal gland autoimmunity in NOD mice. Utilizing IL-27Rα KO NOD mice, I have previously found both CD4 and CD8 effector T cells require IL-27 to transfer lacrimal gland autoimmunity to NOD-SCID mice. Here, we utilized an adoptive co-transfer system that promotes infiltration of lacrimal glands by both WT and IL-27Ra KO T cells to define the T cell intrinsic effects of IL-27 signaling in lacrimal gland infiltrating T cells through 28 color spectral flow cytometry and performed unsupervised dimensionality reduction analyses to identify subsets of T cells reliant on intrinsic IL-27 signaling. Among the total concatenated T cell population including both WT and KO T cells, 12 total subsets were identified. Strikingly, when visualizing WT and KO separately, we identified populations of CD4 effector T cells and CD8 T cells that were either heavily skewed or only present in WT. Through phenotyping these populations, I found IL-27 signaling induced Tfh-like PD-1+ICOS+ CD4 effector T cells and PD-1+ICOS+CD39+ exhausted-like CD8 T cells in the glands of recipient mice. Taken together, these data demonstrate a role for IL-27 in promoting pathogenic T cells in the immune dysregulation of Sjögren’s. Supported by grants from NIH(T32 AI007485, R01 EY027731)