CD8 + cells regulate the T helper-17 response in an experimental murine model of Sjögren syndrome

INTRODUCTION Inflammation mediated by CD4þ T cells has a prominent role in many immunologic disorders. T helper-1 (Th1), Th2, and Th17 populations may each be involved in inflammatory processes, reflecting distinct modes of T-cell recruitment, and divergent mechanisms of inflammatory tissue damage. Native immune/inflammatory processes are constrained by active cellular quiescence and immunologic tolerance, which offers potential therapeutic approach for enduring control of inflammatory disease. Several regulatory T cells (Tregs) subtypes have been described within each of the two main subcategories, CD4þ Treg and CD8þ Treg. Several subsets of inhibitory CD8þ Treg have been identified, some of which may have immunotherapeutic values. Evidence has accumulated that specialized CD8þ Treg have the potential to suppress host injurious responses that develop in autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. The Th17 lineage has been found be distinct from traditional Th1 and Th2 lineages. Interleukin-17A (IL-17A)-producing Th17 cells have been identified as a key effector in a variety of human and experimental autoimmune diseases, including Sjogren syndrome (SS), multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and psoriasis. Keratoconjunctivitis sicca (KCS) in SS is a severe and potentially sight-threatening ocular surface epithelial disease. The pathogenesis of KCS in our mouse model of SS is a multifactorial process that includes activation of stress pathways in the ocular surface epithelia by the hyperosmolar tear film and cytokines produced by resident intraepithelial lymphocytes and infiltrating Th1 and Th17 cells. In this model, we previously demonstrated that desiccating stress (DS)-activated CD4þ T cells when adoptively transferred to naive T-cell-deficient nude mice, were sufficient to elicit autoimmune lacrimal KCS with features resembling human SS, suggesting that CD4þ T cells make a prominent contribution