Pituitary CD8+ T cells in a mouse model of hypophysitis Paulina Chalan1, Shey-Cherng Tzou2, Patrizio Caturegli1, 1Division of Immunology, Department of Pathology, Johns Hopkins School of Medicine; 2Department of Biological Science and Technology, National Chiao Tung University, Taiwan
Hypophysitis is an auto-inflammatory disease of the pituitary gland characterized by infiltration with immune cells, destruction of pituitary endocrine cells, and subsequent hypopituitarism. Hypophysitis can occur spontaneously (primary forms) or in association with the use of immune checkpoint inhibitors for treating several types of cancer (secondary forms). Cancer patients who receive monoclonal antibodies blocking CTLA-4, PD-1, and/or PDL-1 develop hypophysitis at an incidence of about 10%. The pathogenesis of hypophysitis remains poorly understood, in part due to the difficulty in obtaining a pituitary gland biopsy. To further our understanding, we have previously developed a mouse model of the disease based on the injection of whole mouse pituitary proteins mixed with Complete Freund's Adjuvant (CFA) into SJL female mice. Here we used that hypophysitis mouse model to characterize by flow cytometry the lymphoid subsets present in the pituitary gland and draining cervical lymph nodes. Ten mice were injected twice with pituitary proteins in CFA (cases) and 11 mice with CFA only (controls). All mice were sacrificed 35 days after the initial immunization to prepare individual single cell suspensions from pituitary glands and lymph nodes for flow cytometric analysis. Cells were stained using markers for CD4+ and CD8+ T cells (phenotypically divided into naïve, central memory, effector memory, regulatory T cells, and T cells), B cells, NK cells, neutrophils, eosinophils, dendritic cells, macrophages, monocytes (phenotypically divided into inflammatory [Ly6C+CCR2+] and tissue-resident [Ly6C-CCR2-] monocytes). We found that CD8+ T cells were significantly more numerous in cases than in controls (both in the lymph nodes and pituitary glands). In the pituitary gland, these CD8+ T cells were enriched with the effector memory (CD44+CD62L-) subset. The other immune cell populations, on the contrary, did not differ between cases and controls. Our novel findings highlight a role for CD8+ T cells in the pathogenesis of hypophysitis, and serve as a basis to comprehensively analyze their function, clonal repertoire, and autoantigenic specificity.
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