Dendritic cells with TGF-β1 and IL-2 differentiate naive CD4+ T Cells into alloantigen-specific and allograft protective foxp3+ regulatory T cells

Hua Yang, Elaine Y. Cheng, Vijay K. Sharma, Mila Lagman, Christina Chang, Ping Song, Ruchuang Ding, Thangamani Muthukumar, Manikkam Suthanthiran

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background: Naturally occurring, thymic-derived Foxp3+CD25+CD4+ regulatory T cells (nTregs) are pivotal for the maintenance of self-tolerance. nTregs, however, are sparse and lack alloantigen specificity, and these properties pose challenges for their use in clinical transplantation. Methods: We established mixed leukocyte reaction (MLR) with dendritic cells (DCs) as stimulators and CD4+ T cells as responders and supplemented the MLR with IL-2 and TGF-β1 and investigated whether DCs+IL-2+TGF-β1 differentiate the polyclonal CD4+ cells into alloantigen-specific and allograft protective Tregs. Results: We found a greater than a 10-fold increase in Foxp3+CD25+ subpopulation (P<0.01) following stimulation of BALB/c CD4+ cells with C57BL/6 (B6) CD11c+ DCs+IL-2+TGF-β1 in the MLR. Levels of TGF-β1 messenger RNA (mRNA) (P=0.01) and the ratios of TGF-β1 mRNA to granzyme B mRNA (P=0.0003) and Foxp3 mRNA to granzyme B mRNA (P<0.01) were higher in alloantigen-induced Tregs (alloTregs) compared with nTregs. alloTregs suppressed MLR at a 16:1 responder to suppressor ratio, whereas nTregs suppressed at 4:1. Suppression by alloTregs was alloantigen specific and was observed at the level of responder cells and at the level of stimulator cells. In a fully H-2-mismatched, nonlymphopenic, immunocompetent mouse islet transplantation model, alloTregs but not nTregs prolonged survival of islet allografts without any other immunosuppressive therapy (P=0.0003), and the protection was alloantigen specific. Conclusions: A combination of CD11c+ DCs, IL-2, and TGF-β1 may help differentiate naive, high abundant CD4+ T into alloantigen-specific and allograft protective Foxp3+Tregs.

Original languageEnglish
Pages (from-to)580-588
Number of pages9
JournalTransplantation
Volume93
Issue number6
DOIs
Publication statusPublished - 27 Mar 2012

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Keywords

  • Dendritic cells
  • Foxp3
  • Islet cell transplantation
  • Regulatory T cells

ASJC Scopus subject areas

  • Transplantation

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