Molecular Mechanism of Sphingosine-1-Phosphate Receptor 1 Regulating CD4+ Tissue Memory in situ T Cells in Primary Sjogren’s Syndrome

Abstract

Objective Although extensive research has been carried out on CD4 + T cells infiltrating the labial glands in patients with primary Sjögren’s Syndrome (pSS), it is still unclear how CD4 + T cells remain in the labial gland tissue and develop into tissue resident cells. The aim of this study was to investigate the molecular mechanism by which CD4 + T reside in labial glandular tissue of pSS patients. Methods Lymphocyte infiltration in labial salivary glands (LSG) of pSS patients was detected by H&E staining. Expression of sphingosine-1-phosphate receptor 1 (S1PR1) in LSG was examined by Immunohistochemistry. Immunofluorescence analyses were utilized to detect the co-expression of CD4, CD69 and S1PR1 in T cells of LSG of pSS patients. Expression of gene S1pr1 in peripheral blood CD4 + T cells of healthy controls and pSS patients was detected by quantitative real-time PCR (QPCR). QPCR was used to examine the expression of gene S1pr1, Klf2, and Cd69 in the CD4 + T cells that were co-cultured in vitro with cytokines TNF-α, TGF-β, and IL-33. Results S1PR1 was expressed in the infiltrating monocytes in LSG of pSS patients, and S1PR1 was weakly or even not expressed in cytoplasm of CD4 + CD69 + T RM cells of LSG in patients with pSS. Expression of gene S1pr1 in peripheral blood CD4 + T cells of pSS patients was about three-fifths of that of healthy controls (P < 0.05). Expression of genes S1pr1 (P < 0.001) and Klf-2 (P < 0.001) was significantly decreased, and the expression of gene Cd69 (P < 0.05) was significantly increased in peripheral blood CD4 + T cells of pSS patients co-cultured in vitro with cytokines TNF-α, TGF-β, and IL-33. Conclusion Our study suggests that the decrease of S1pr1 gene expression may provide a molecular basis for promoting the tissue retention and development of CD4 + CD69 + T RM cells.

Virus-Associated CD8 + T-Cells Are Not Activated Through Antigen-Mediated Interaction Inside Atherosclerotic Lesions

“…To evaluate phenotypic changes in situ, virus-associated CD8 + T-cells from blood were compared with their counterparts in the atherosclerotic lesion (Figure 2C). The transition from the blood toward the proinflammatory environment of the lesion results in the downregulation of genes associated with tissue egress, 37 apparent from a reduced expression of S1PR1 , and KLF2 in virus-associated CD8 + T-cells in the atherosclerotic lesion (Figure 2C and 2E). Interestingly, virus-associated CD8 + T-cells in the lesion also had a more activated phenotype, based on the increased expression of genes associated with TCR stimulation, including FOS, JUN, FOSB, CD69 , and JUND and decreased expression of CSK (Figure 2C and 2D).…”

Outline of Salivary Gland Pathogenesis of Sjögren’s Syndrome and Current Therapeutic Approaches

“…High S1P concentrations in blood vessels and the lymphatic circulatory system and low S1P concentrations in the thymus and lymph nodes form a gradient that facilitates the migration of lymphocytes from peripheral lymphoid organs to the circulatory system via S1PR1. Due to the central role of S1P in lymphocyte transport, S1PR1 has been implicated in autoimmune diseases and cancer [ 237 , 238 , 239 ]. Fingolimod (FTY720) is structurally similar to sphingosine and is phosphorylated by sphingosine kinase 2.…”