Dendritic cells with TGF-?1 and IL-2 differentiate naive CD4+ T cells into alloantigen-specific and allograft protective Foxp3+ regulatory T cells.

ABSTRACT: 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.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-?1 and investigated whether DCs+IL-2+TGF-?1 differentiate the polyclonal CD4+ cells into alloantigen-specific and allograft protective Tregs.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-?1 in the MLR. Levels of TGF-?1 messenger RNA (mRNA) (P=0.01) and the ratios of TGF-?1 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.A combination of CD11c+ DCs, IL-2, and TGF-?1 may help differentiate naive, high abundant CD4+ T into alloantigen-specific and allograft protective Foxp3+Tregs.

SUBMITTER: Yang H 

PROVIDER: S-EPMC3595618 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature