Identification of Novel CD4+ T Cell Subsets in the Target Tissue of Sjögren's Syndrome and Their Differential Regulation by the Lymphotoxin/LIGHT Signaling Axis

Abstract

Despite being one of the most common rheumatologic diseases, there is still no disease-modifying drug for primary Sjögren's syndrome (pSS). Advancing our knowledge of the target tissue has been limited by the low dimensionality of histology techniques and the small size of human salivary gland biopsies. In this study, we took advantage of a molecularly validated mouse model of pSS to characterize tissue-infiltrating CD4⁺ T cells and their regulation by the lymphotoxin/LIGHT signaling axis. Novel cell subsets were identified by combining highly dimensional flow and mass cytometry with transcriptomic analyses. Pharmacologic modulation of the LTβR signaling pathway was achieved by treating mice with LTβR-Ig, a therapeutic intervention currently being tested in pSS patients (Baminercept trial NCT01552681). Using these approaches, we identified two novel CD4⁺ T cell subsets characterized by high levels of PD1: Prdm1⁺ effector regulatory T cells expressing immunoregulatory factors, such as Il10, Areg, Fgl2, and Itgb8, and Il21⁺ effector conventional T cells expressing a pathogenic transcriptional signature. Mirroring these observations in mice, large numbers of CD4⁺PD1⁺ T cells were detected in salivary glands from Sjögren's patients but not in normal salivary glands or kidney biopsies from lupus nephritis patients. Unexpectedly, LTβR-Ig selectively halted the recruitment of PD1^- naive, but not PD1⁺, effector T cells to the target tissue, leaving the cells with pathogenic potential unaffected. Altogether, this study revealed new cellular players in pSS pathogenesis, their transcriptional signatures, and differential dependency on the lymphotoxin/LIGHT signaling axis that help to interpret the negative results of the Baminercept trial and will guide future therapeutic interventions.