Immunomodulatory effects of umbilical mesenchymal stem cell-derived exosomes on CD4+ T cells in patients with primary Sjögren's syndrome

Abstract

Background: Primary Sjögren's syndrome (pSS) is an autoimmune disease that leads to the destruction of exocrine glands and multisystem lesions. Abnormal proliferation, apoptosis, and differentiation of CD4⁺ T cells are key factors in the pathogenesis of pSS. Autophagy is one of the important mechanisms to maintain immune homeostasis and function of CD4⁺ T cells. Human umbilical cord mesenchymal stem cell-derived exosomes (UCMSC-Exos) may simulate the immunoregulation of MSCs while avoiding the risks of MSCs treatment. However, whether UCMSC-Exos can regulate the functions of CD4⁺ T cells in pSS, and whether the effects via the autophagy pathway remains unclear.

Methods: The study analyzed retrospectively the peripheral blood lymphocyte subsets in pSS patients, and explored the relationship between lymphocyte subsets and disease activity. Next, 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 and genes were detected using western blotting or RT-qPCR.

Results: The study demonstrated that the peripheral blood CD4⁺ T cells decreased in pSS patients, and negatively correlated with disease activity. UCMSC-Exos inhibited excessive proliferation and apoptosis of CD4⁺ T cells in pSS patients, blocked them in the G0/G1 phase, inhibited them from entering the S phase, reduced the Th17 cell ratio, elevated the Treg ratio, inhibited IFN-γ, TNF-α, IL-6, IL-17A, and IL-17F secretion, and promoted 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, inhibited Th17 cell differentiation, promoted Treg cell differentiation, and restored the Th17/Treg balance in pSS patients through the autophagy pathway.

Conclusions: The study indicated that UCMSC-Exos exerts an immunomodulatory effect on the CD4⁺ T cells, and maybe as a new treatment for pSS.

Keywords: Autophagy; CD4+ T cell; Exosome; Mesenchymal stem cell; Sjögren's syndrome.