CD8 T cells contribute to lacrimal gland pathology in the nonobese diabetic mouse model of Sjögren syndrome

Abstract

Sjögren syndrome is an autoimmune disease characterized by targeted destruction of the lacrimal and salivary glands resulting in symptoms of severe ocular and oral dryness. Despite its prevalence, the mechanisms driving autoimmune manifestations are unclear. In patients and in the nonobese diabetic (NOD) mouse model of Sjögren syndrome, lymphocytic infiltrates consist of CD4 and CD8 T cells, although the role of CD8 T cells in disease pathogenesis has been largely unexplored. Here, we evaluated the contribution of CD8 T cells to lacrimal and salivary gland autoimmunity. Within the lacrimal and salivary glands of NOD mice, CD8 T cells were proliferating, expressed an activated phenotype, and produced inflammatory cytokines. Transfer of purified CD8 T cells isolated from the cervical lymph nodes (LN) of NOD mice into NOD-SCID recipients resulted in inflammation of the lacrimal glands, but was not sufficient to cause inflammation of the salivary glands. Lacrimal gland-infiltrating CD8 T cells displayed a cytotoxic phenotype, and epithelial cell damage in the lacrimal glands was observed in recipients of CD8 T cells regardless of the presence of CD4 T cells. Collectively, our results demonstrate that CD8 T cells play a pathogenic role in lacrimal gland autoimmunity. The gland-specific pathogenicity of CD8 T cells makes them a valuable resource to further understand the mechanisms that discriminate lacrimal versus salivary gland autoimmunity and for the development of new therapeutics that target the early stages of disease.

Tissue‐Resident Memory CD8+ T Cells Acting as Mediators of Salivary Gland Damage in a Murine Model of Sjögren's Syndrome

“…CD8+ T cells localize around the apoptotic acinar epithelial cells in patients with SS (). Another recent study found that CD8+ T cells can promote dacryoadenitis and mediate epithelial cell damage in NOD mice . In this study, we found that CD8+ T cells were dominant both in the labial salivary glands of patients with SS and in the salivary glands of p40 −/− CD25 −/− mice.…”

“…Genome‐wide association scans and meta‐analyses of SS have revealed a strong association of the disease with several HLA molecules , implicating T cells as a major driver of SS. Although previous studies have found that CD4+ T cells constitute the majority of infiltrating cells, recent findings have suggested that CD8+ T cells are just as abundant as CD4+ T cells and may play an equally critical role in SS . However, the CD8+ T cell subpopulations implicated in the pathologic development and progression of SS have not yet been identified.…”

Salivary‐gland‐protective regulatory T‐cell dysfunction underlies female‐specific sialadenitis in the non‐obese diabetic mouse model of Sjögren syndrome

“…Male and female NOD/ShiLtJ (NOD), castrated and sham‐castrated male NOD, and NOD.CB17‐ Prkdc scid / J (non‐obese diabetic– severe combined immunodeficient; NOD‐SCID) mice were purchased from The Jackson Laboratory (Bar Harbor, ME). NOD mice expressing the bicistronic Foxp3‐green fluorescent protein (Foxp3 GFP ) reporter construct knocked into the endogenous Foxp3 locus (NOD), were a kind gift from Vijay Kuchroo (Harvard University, Cambridge, MA) and were previously described . Mice used for phenotypic analyses of salivary gland infiltrating cells were 14‐ to 15‐week‐old females and 19‐ to 21‐week‐old males.…”

“…Inflammation of submandibular salivary glands and exorbital lacrimal glands was quantified as previously described . Briefly, glands were formalin‐fixed, processed and embedded in paraffin.…”

“…Five‐micrometre sections were stained with haematoxylin & eosin and analysed by standard light microscopy. Inflammation was quantified by a blinded observer using standard focus scoring as previously described with focus score reported as number of foci (aggregates of 50 or more mononuclear cells) per 4‐mm 2 tissue area. Tissue areas were measured using either Nikon nis‐elements br 3.1 software or imagej software as previously described .…”