TGF-β3-expressing CD4+CD25(-)LAG3+ regulatory T cells control humoral immune responses

Nat Commun. 2015 Feb 19;6:6329. doi: 10.1038/ncomms7329.

Abstract

Autoantibodies induce various autoimmune diseases, including systemic lupus erythematosus (SLE). We previously described that CD4(+)CD25(-)LAG3(+) regulatory T cells (LAG3(+) Treg) are regulated by Egr2, a zinc-finger transcription factor required for the induction of T-cell anergy. We herein demonstrate that LAG3(+) Treg produce high amounts of TGF-β3 in an Egr2- and Fas-dependent manner. LAG3(+) Treg require TGF-β3 to suppress B-cell responses in a murine model of lupus. Moreover, TGF-β3- and LAG3(+) Treg-mediated suppression requires PD-1 expression on B cells. We also show that TGF-β3-expressing human LAG3(+) Treg suppress antibody production and that SLE patients exhibit decreased frequencies of LAG3(+) Treg. These results clarify the mechanism of B-cell regulation and suggest therapeutic strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • B-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / cytology*
  • Disease Models, Animal
  • Early Growth Response Protein 2 / metabolism*
  • Female
  • Humans
  • Immunity, Humoral / immunology*
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Lupus Erythematosus, Systemic / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Spleen / metabolism
  • T-Lymphocytes, Regulatory / cytology
  • Transforming Growth Factor beta3 / metabolism*

Substances

  • Antigens, CD
  • CD223 antigen
  • EGR2 protein, human
  • Early Growth Response Protein 2
  • Egr2 protein, mouse
  • IL2RA protein, human
  • Interleukin-2 Receptor alpha Subunit
  • TGFB3 protein, human
  • Tgfb3 protein, mouse
  • Transforming Growth Factor beta3