CD4+CD25+ T cells alloactivated ex vivo by IL-2 or IL-4 become potent alloantigen-specific inhibitors of rejection with different phenotypes, suggesting separate pathways of activation by Th1 and Th2 responses

Nirupama Darshan Verma, Karren Michelle Plain, Masaru Nomura, Giang T Tran, Catherine M Robinson, Rochelle Boyd, Suzanne J Hodgkinson, Bruce M Hall

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35 Citations (Scopus)


CD4(+)CD25(+)Foxp3(+) T cells are regulatory/suppressor cells (Tregs) that include non-antigen (Ag)-specific as well as Ag-specific Tregs. How non-Ag-specific naive CD4(+)CD25(+) Treg develop into specific Tregs is unknown. Here, we generated adaptive Tregs by culture of naive CD4(+)CD25(+)Foxp3(+) T cells with allo-Ag and either interleukin-2 (IL-2) or IL-4. Within days, IL-2 enhanced interferon-gamma receptor (Ifngammar) and Il-5 mRNA and IL-4 induced a reciprocal profile with de novo IL-5Ralpha and increased IFN-gamma mRNA expression. Both IL-2- and IL-4-alloactivated CD4(+)CD25(+) Tregs within 3 to 4 days of culture had enhanced capacity to induce tolerance to specific donor but not to third-party cardiac allografts. These hosts became tolerant as allografts functioned more than 250 days, with a physiologic ratio of less than 10% CD4(+)CD25(+)Foxp3(+) T cells in the CD4(+) population. CD4(+)CD25(+) T cells from tolerant hosts given IL-2-cultured cells had increased Il-5 and Ifngammar mRNA. Those from hosts given IL-4-cultured cells had enhanced IL-5Ralpha mRNA expression and IL-5 enhanced their proliferation to donor but not third-party allo-Ag. Thus, IL-2 and IL-4 activated allo-Ag-specific Tregs with distinct phenotypes that were retained in vivo. These findings suggested that T-helper 1 (Th1) and Th2 responses activate 2 pathways of adaptive Ag-specific Tregs that mediate tolerance. We propose they be known as T-suppressor 1 (Ts1) and Ts2 cells.

Original languageEnglish
Pages (from-to)479-87
Number of pages9
Issue number2
Publication statusPublished - 8 Jan 2009
Externally publishedYes



  • Animals
  • Caspase 1
  • Cytokines
  • Graft Rejection
  • Heart Transplantation
  • Interleukin-2
  • Isoantigens
  • Lymphocyte Activation
  • Myocardium
  • Phenotype
  • RNA, Messenger
  • Rats
  • Rats, Inbred Lew
  • Receptors, Interferon
  • T-Lymphocytes, Regulatory
  • Th1 Cells
  • Th2 Cells
  • Time Factors
  • Transplantation Tolerance
  • Journal Article
  • Research Support, Non-U.S. Gov't

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