CD8+CD103+ iTregs Inhibit Chronic Graft-versus-Host Disease with Lupus Nephritis by the Increased Expression of CD39

Abstract

Many patients with systemic lupus erythematosus (SLE) have lupus nephritis, one of the severe complications of SLE. We previously reported that CD8+CD103+ T regulatory cells induced ex vivo with transforming growth factor β (TGF-β) (iTregs) inhibited immune cells responses to ameliorate excessive autoimmune inflammation. However, the molecular mechanism(s) underlying the role of these CD8+ iTregs is still unclear. Here we identified that CD39, which is highly expressed on CD8+ iTregs, crucially contributes to the immunosuppressive role of the CD8+CD103+ iTregs. We showed that adoptive transfer of CD8+CD103+ iTregs significantly relieves the chronic graft-versus-host disease with lupus nephritis and CD39 inhibitor mostly abolished the functional activities of these CD8+ iTregs in vitro and in vivo . CD39+ cells sorted from CD8+CD103+ iTregs were more effective in treating lupus nephritis than CD39− partner cells in vivo . Furthermore, human CD8+ iTregs displayed increased CD103 and CD39 expressions, and CD39 was involved in the suppressive function of human CD8+ iTregs. Thus, our data implicated a crucial role of CD39 in CD8+CD103+ iTregs in treating lupus nephritis, and CD39 could be a new phenotypic biomarker for the identification of highly qualified CD8+ Tregs. This subpopulation may have therapeutic potential in patients with SLE nephritis and other autoimmune diseases.

Regulatory T Cell Therapy of Graft-versus-Host Disease: Advances and Challenges

“…The defining markers of CD8 iTregs are still under study and more research will be necessary to reach a consensus [78]. CD8 iTregs have been reported to engage in multiple cell-dependent and independent mechanisms to mediate immune suppression and homeostasis [79][80][81][82][83]. Using mice that were unable to generate both CD4 and CD8 iTregs, Beres et al showed that iTreg-deficient mice had increased expansion of alloreactive T cells, and that CD8 iTregs in the absence of CD4 iTregs had the capacity to prevent GVHD severity [77].…”

Magnetic nanoparticles: A new diagnostic and treatment platform for rheumatoid arthritis

“…Various suppressor cells including mesenchymal stem cells (MSCs) and regulatory T cells (Treg) have been widely considered as a new treatment tool for autoimmune diseases, 78,79 such as graft-versus-host disease (GvHD), [80][81][82] systemic lupus erythematosus (SLE), 83,84 allergic diseases, 85,86 type I diabetes, 87 and multiple sclerosis (MS). 88,89 Particularly, the properties of increasing the ratio of Treg/Th17, as well as differentiating into osteoblasts and chondrocytes, are significant for RA treatment.…”

Association of the ENPP1/ENTPD1 Polymorphisms in Hemodialysis Patients

“…Meanwhile, it has been established that adenosine can inhibit the advancement of renal fibrosis through a combination of A2A and A2B receptors on renal tubular endothelial cells. 31 Treg cells or macrophages were involved in renal protection mediated by CD39, 32,33 even though the macrophages were also one of the main inflammatory cells in kidney injury. Overexpression CD39 fails to protect against renal fibrosis.…”