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

Mol Ther. 2019 Nov 6;27(11):1963-1973. doi: 10.1016/j.ymthe.2019.07.014. Epub 2019 Jul 26.

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.

Keywords: CD39; CD8; T regulatory cell; lupus nephritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / metabolism*
  • Apyrase / metabolism*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cell Differentiation
  • Cell Proliferation
  • Chronic Disease
  • Graft vs Host Disease / etiology*
  • Graft vs Host Disease / prevention & control
  • Graft vs Host Disease / therapy
  • Humans
  • Immune Tolerance
  • Immunomodulation
  • Integrin alpha Chains / metabolism*
  • Lupus Nephritis / etiology*
  • Lupus Nephritis / prevention & control
  • Lupus Nephritis / therapy
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*
  • Transforming Growth Factor beta / metabolism

Substances

  • Antigens, CD
  • Integrin alpha Chains
  • Transforming Growth Factor beta
  • alpha E integrins
  • Apyrase
  • ENTPD1 protein, human