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Blood, 8 January 2009, Vol. 113, No. 2, pp. 479-487. Prepublished online as a Blood First Edition Paper on September 30, 2008; DOI 10.1182/blood-2008-05-156612. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-05-156612v1 113/2/479    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Verma, N. D. Articles by Hall, B. M. Search for Related Content PubMed PubMed Citation Articles by Verma, N. D. Articles by Hall, B. M. Related Collections Transplantation Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  TRANSPLANTATION 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 D. Verma*,1, Karren M. Plain*,1, Masaru Nomura1, Giang T. Tran1, Catherine Robinson1, Rochelle Boyd1, Suzanne J. Hodgkinson1, and Bruce M. Hall1 1 Faculty of Medicine, University of New South Wales and Department of Medicine, Liverpool Hospital, Liverpool, Australia 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- receptor (Ifnr) and Il-5 mRNA and IL-4 induced a reciprocal profile with de novo IL-5R and increased IFN- 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 Ifnr mRNA. Those from hosts given IL-4–cultured cells had enhanced IL-5R 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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