Background Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by autoantibody production and mesenchymal stem cells (MSCs) have emerged as a promising new therapy for the treatment of SLE. MSCs are adult stem cells isolated from various human tissues including bone marrow, adipose tissue, umbilical cord blood, and skeletal muscle; MSCs can differentiate into various cell types and can potentially replace damaged cells in vivo. MSCs suppress T cell proliferation and cytokine production, reduce B cell proliferation and antibody secretion, decrease the generation and function of dendritic cells, and reduce the activity of natural killer cells. MSCs also enhance the activity of regulatory T (Treg) cells. MSCs are thought to inhibit T cell functions by two different mechanisms: by producing soluble mediators and by direct cellcell contacts. The soluble immunosuppressive factors produced by MSCs include IL-10, nitric oxide (NO), tumor growth factor (TGF)-, prostaglandin E2 (PGE2), and indoleamine 2,3-dioxygenase (IDO), all of which can inhibit the functions of major immune cells. Yet, much remains to be learned about the contact-dependent T cell inhibition by MSCs.
Methods We examined the in vivo efficacy of MSCs in lupus-prone MRL/lpr mouse model and examined how MSCs inhibit MRL/lpr T cells by using time-lapse imaging at the single level.
Results In this study, we show that transfer of human MSCs increased MRL/lpr mouse survival, decreased T cell infiltration in the kidneys, and reduced T cell cytokine expression. In vitro, allogeneic mouse MSCs inhibited MRL/lpr T cell proliferation and cytokine production. Time-lapse imaging revealed that MSCs recruited MRL/lpr T cells establishing long-lasting cellular contacts by enhancing T cell VCAM-1 expression in a CCL2-dependent manner. In contrast, CCL2 deficient MSCs did not induce T cell migration and VCAM-1 expression, resulting in insufficient cell-cell contact. Consequently, CCL2 deficient MSCs did not inhibit IFN- production by T cells and upon transfer no longer prolonged survival of MRL/lpr mice.
Conclusions Taken together, our imaging study demonstrates that CCL2 enables the prolonged MSC-T cell interactions needed for sufficient suppression of autoreactive T cells and helps to understand how MSCs ameliorate symptoms in lupus-prone MRL/lpr mice.
Funding Source(s): This study was supported by grants funded by the KoreanGovernment (NRF-2017R1A5A2015541 and NRF-2017M3A9B4050336).
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