Umbilical Mesenchymal Stem Cell-derived Exosomes Regulate CD4+ T cells in Patients with Primary Sjogren's Syndrome through the Autophagy Pathway

Abstract

Background: Primary Sjögren's syndrome (pSS) is an autoimmune disease that leads to the destruction of exocrine glands and formation of multisystem lesions. Abnormal proliferation, apoptosis, and differentiation of CD4+ T cells are key factors in the pathogenesis of pSS, seriously affecting the appearance, progression, and outcome of the disease. Human umbilical cord mesenchymal stem cell-derived exosomes (UCMSC-Exos) may effectively simulate the immunoregulatory and tissue repair functions of MSCs while avoiding the risks associated with MSCs treatment. Hence, UCMSC-Exos treatment is expected to become a new treatment for pSS. However, if UCMSC-Exos can regulate the abnormal proliferation, apoptosis, and differentiation of CD4+ T cells in pSS and the specific underlying mechanisms remain to be elucidated. Methods: UCMSC-Exos were isolated and identified. Peripheral blood CD4+ T-cells were sorted using immunomagnetic beads. The proliferation, apoptosis, differentiation, and inflammatory factors of CD4+ T cells were determined using flow cytometry. Autophagosomes of CD4+ T cells were detected using transmission electron microscopy, autophagy-related proteins were detected using western blotting, and autophagy-related genes were detected using RT-PCR. Results: UCMSC-Exos inhibited excessive proliferation of peripheral blood CD4+ T cells in pSS patients, blocked the G0/G1 phase transition, inhibited S phase cells, suppressed excessive apoptosis of CD4+ T cells, reduced the Th17 cell ratio, elevated the regulatory T cell (Treg) ratio, restored the Th1/Th2 and Th17/Treg balance, inhibited the CD4+ T cell-associated pro-inflammatory factors IFN-γ, TNF-α, IL-6, IL-17A, and IL-17F secretion, and promoted anti-inflammatory factor IL-10 and TGF-β secretion. UCMSC-Exos reduced the elevated autophagy levels in the peripheral blood CD4+ T cells of patients with pSS. Furthermore, UCMSC-Exos regulated CD4+ T cell proliferation and early apoptosis in pSS patients through the autophagy pathway, inhibited Th17 cell differentiation, promoted Treg cell differentiation, and restored the Th17/Treg balance. Conclusions: UCMSC-Exos regulate CD4+ T cell proliferation, apoptosis, and differentiation in patients with pSS through the autophagy pathway and exhibit immunoregulatory effects. These results provide an important theoretical and experimental foundation for exploring UCMSC-Exos as a new treatment for pSS and its application in clinical transformation.