Aging, Sex Bias, and CD8 T Cell Exhaustion in Salivary Gland Inflammation

PROJECT SUMMARY Sjögren’s Disease (SjD) is a systemic autoimmune disorder most frequently targeting exocrine glands and causing oral and ocular dryness. SjD is characterized by serum antibodies to nuclear and cytoplasmic antigens and salivary gland inflammation (sialoadenitis), which is associated with an increased risk of lymphoma. For unknown reasons, SjD disproportionately affects females and is typically diagnosed in the 5th- 6th decade of life. Thus, female sex and aging are intricately linked with immune dysfunction and autoimmunity in SjD. The long-term goal of this project is to understand the age- and sex-related immune mechanisms involved in the salivary gland pathology of SjD. The proposed studies will utilize male and female mice that spontaneously develop the salient characteristics of SjD and mimic the age- and sex-bias of the disease. While both males and females develop systemic autoimmunity, only the females progress to severe sialoadenitis. We will use a conceptually innovative approach by investigating the immunoregulatory mechanisms that protect males from severe sialoadenitis. Aim 1 will investigate whether the aged male salivary gland microenvironment harbors immunosuppressive signals that inhibit progressive inflammation. We will characterize gene expression changes in immune, epithelial, and stromal compartments using single- cell transcriptomic profiling of male and female salivary glands at key aging milestones. Recent literature suggests a prominent role for CD8 T cells in the glandular pathology of SjD. Aim 2 will examine the differentiation trajectory of CD8 T cells targeting salivary gland antigens in male and female mice. We will leverage a novel mouse model expressing ovalbumin as a surrogate self-antigen in the salivary glands to track antigen-specific CD8 T cell activation. Our findings will inform the development of innovative therapeutic strategies aimed at local immune modulation to alleviate salivary gland pathology in SjD.