Segregated regulatory CD39+CD4+ T cell function: TGF-β-producing Foxp3- and IL-10-producing Foxp3+ cells are interdependent for protection against collagen-induced arthritis

J Immunol. 2011 Nov 1;187(9):4654-66. doi: 10.4049/jimmunol.1100530. Epub 2011 Oct 3.

Abstract

Oral immunization with a Salmonella vaccine vector expressing enterotoxigenic Escherichia coli colonization factor Ag I (CFA/I) can protect against collagen-induced arthritis (CIA) by dampening IL-17 and IFN-γ via enhanced IL-4, IL-10, and TGF-β. To identify the responsible regulatory CD4(+) T cells making the host refractory to CIA, Salmonella-CFA/I induced CD39(+)CD4(+) T cells with enhanced apyrase activity relative to Salmonella vector-immunized mice. Adoptive transfer of vaccine-induced CD39(+)CD4(+) T cells into CIA mice conferred complete protection, whereas CD39(-)CD4(+) T cells did not. Subsequent analysis of vaccinated Foxp3-GFP mice revealed the CD39(+) T cells were composed of Foxp3-GFP(-) and Foxp3-GFP(+) subpopulations. Although each adoptively transferred Salmonella-CFA/I-induced Foxp3(-) and Foxp3(+)CD39(+)CD4(+) T cells could protect against CIA, each subset was not as efficacious as total CD39(+)CD4(+) T cells, suggesting their interdependence for optimal protection. Cytokine analysis revealed Foxp3(-) CD39(+)CD4(+) T cells produced TGF-β, and Foxp3(+)CD39(+)CD4(+) T cells produced IL-10, showing a segregation of function. Moreover, donor Foxp3-GFP(-) CD4(+) T cells converted to Foxp3-GFP(+) CD39(+)CD4(+) T cells in the recipients, showing plasticity of these regulatory T cells. TGF-β was found to be essential for protection because in vivo TGF-β neutralization reversed activation of CREB and reduced the development of CD39(+)CD4(+) T cells. Thus, CD39 apyrase-expressing CD4(+) T cells stimulated by Salmonella-CFA/I are composed of TGF-β-producing Foxp3(-) CD39(+)CD4(+) T cells and support the stimulation of IL-10-producing Foxp3(+) CD39(+)CD4(+) T cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, CD / biosynthesis
  • Antigens, CD / physiology*
  • Apyrase / biosynthesis
  • Apyrase / physiology*
  • Arthritis, Experimental / immunology*
  • Arthritis, Experimental / pathology
  • Arthritis, Experimental / prevention & control
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Collagen / administration & dosage
  • Collagen / toxicity*
  • Fimbriae Proteins
  • Forkhead Transcription Factors / biosynthesis
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / physiology*
  • Interleukin-10 / biosynthesis
  • Interleukin-10 / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Salmonella Vaccines / administration & dosage
  • Salmonella Vaccines / immunology
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytes, Regulatory / transplantation
  • Transforming Growth Factor beta / biosynthesis*
  • Vaccines, DNA / administration & dosage
  • Vaccines, DNA / immunology

Substances

  • Antigens, CD
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Salmonella Vaccines
  • Transforming Growth Factor beta
  • Vaccines, DNA
  • colonization factor antigens
  • Interleukin-10
  • Fimbriae Proteins
  • Collagen
  • Apyrase
  • CD39 antigen