Activation Molecule Family Receptors Research Articles

SLAMF3 promotes Th17 differentiation and is reversed by iguratimod through JAK1/STAT3 pathway in primary Sjögren's syndrome

ObjectiveThe signaling lymphocytic activation molecule family of receptors (SLAMF) is involved in the activation of T cells and plays important roles in the pathogenesis of autoimmune diseases. The purpose of this study is to observe the expression of SLAMF3 on CD4 + T cells and its effect on the differentiation of T helper 17 (Th17) in primary Sjögren's syndrome (pSS). Furthermore, we found iguratimod (IGU) could effectively reverse the aberrant Th17 differentiation through JAK1/STAT3 signaling. MethodsPeripheral blood mononuclear cells from 40 pSS and 40 healthy control subjects were enrolled for analysis of expression of SLAMF3 on CD4 + T and Th17 cells by flow cytometry. Serum IL-17 and SLAMF3 were detected by ELISA assay. Labial biopsies from 20 pSS patients and 20 non-pSS controls were performed immunohistochemical for staining expression of CD4, IL-17, and SLAMF3. Under the priming conditions with anti-CD3/CD28 or CD3/SLAMF3 antibodies on CD4 + T cells extracted from pSS and controls, the proportion of Th17 cells in CD4 + T cells and the amount of soluble IL-17A were assessed by flow cytometry and ELISA. Furthermore, RNA sequencing was performed for the transcriptomics study. Additionally, RNA level of RORγt and IL-17A and the protein level of RORγt, p-JAK1 and p-STAT3, were detected by real-time PCR and western blot. ResultsThe expression levels of SLAMF3 on CD4 + T and Th17 cells in the peripheral blood and salivary glands in pSS patients were significantly elevated than that in control groups. The serum IL-17A and SLAMF3 in pSS patients were much higher compared with the control group. Although co-stimulation of CD3/SLAMF3 could promote CD4 + T cells differentiate into Th17 cells both in pSS and controls, the CD4 + T cells from pSS have a more sensitive response in Th17 differentiation with the SLAMF3 stimulation. Transcriptomics results showed the CD3/SLAMF3 stimulation caused the activation of Th17 signaling and JAK1/STAT3 pathway. Quantitative PCR and western blotting confirmed the IGU (iguratimod), which is a safe clinical drug in treatment of autoimmune diseases, effectively reversed the increased Th17 proportion, the expression levels of RORγt, pJAK1, and pSTAT3 caused by CD3/SLAMF3 stimulation. ConclusionSLAMF3 upregulates Th17 cell differentiation of CD4 + T cells and IL-17A secretion through enriching RORγt and activating the transcriptomics participating in the pathogenesis of primary Sjögren's syndrome. IGU could inhibit the process through this therapeutic target in pSS.

Role of signaling lymphocytic activation molecule family of receptors in the pathogenesis of rheumatoid arthritis: insights and application.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and joint damage. The signaling lymphocytic activation molecule (SLAMF) family of receptors are expressed on various hematopoietic and non-hematopoietic cells and can regulate both immune cell activation and cytokine production. Altered expression of certain SLAMF receptors contributes to aberrant immune responses in RA. In RA, SLAMF1 is upregulated on T cells and may promote inflammation by participating in immune cell-mediated responses. SLAMF2 and SLAMF4 are involved in regulating monocyte tumor necrosis factor production and promoting inflammation. SLAMF7 activates multiple inflammatory pathways in macrophages to drive inflammatory gene expression. SLAMF8 inhibition can reduce inflammation in RA by blocking ERK/MMPs signaling. Of note, there are differences in SLAMF receptor (SFR) expression between normal and arthritic joint tissues, suggesting a role as potential diagnostic biomarkers. This review summarizes recent advances on the roles of SLAMF receptors 1, 2, 4, 7, and 8 in RA pathogenesis. However, further research is needed to elucidate the mechanisms of SLAMF regulation of immune cells in RA. Understanding interactions between SLAMF receptors and immune cells will help identify selective strategies for targeting SLAMF signaling without compromising normal immunity. Overall, the SLAMF gene family holds promise as a target for precision medicine in RA, but additional investigation of the underlying immunological mechanisms is needed. Targeting SLAMF receptors presents opportunities for new diagnostic and therapeutic approaches to dampen damaging immune-mediated inflammation in RA.

Control of T Lymphocyte Signaling by Ly108, a Signaling Lymphocytic Activation Molecule Family Receptor Implicated in Autoimmunity

The signaling lymphocytic activation molecule family of receptors has been implicated in the pathophysiology of autoimmunity in humans and mice. One member of the family, Ly108, was strongly linked to lupus susceptibility in mice. High expression of a Ly108 isoform, Ly108-1, was observed in lymphocytes of lupus-prone mice. Herein, we examined the molecular basis for the influence of Ly108 on lupus susceptibility by studying Ly108 signal transduction in T cells. We observed that Ly108 was able to mediate a tyrosine phosphorylation signal implicating Ly108, Vav-1, and c-Cbl in a manner strictly dependent on engagement of the extracellular domain of Ly108 and co-expression of the Src homology 2 (SH2) domain-containing adaptor signaling lymphocytic activation molecule (SLAM)-associated protein (SAP). Evaluation of T cells from mice carrying mutations in the SAP-FynT pathway indicated that Ly108-triggered protein tyrosine phosphorylation was due to the capacity of SAP to recruit FynT. Importantly, Ly108-1 was more apt at triggering tyrosine phosphorylation signals in T cells when compared with the predominant Ly108 isoform found in non-lupus-prone mice, Ly108-2. This difference was due in part to the presence in Ly108-1 of a unique intra-cytoplasmic tyrosine-based motif that promoted Ly108 signal transduction. Together these data provided a molecular explanation for the involvement of Ly108 in lupus susceptibility in mice.