A role for TGF-beta in the generation and expansion of CD4(+)CD25(+) regulatory T cells from human peripheral blood

An elusive goal in transplanting organs across histocompatibility barriers has been the induction of specific tolerance to avoid graft rejection. A co nsiderable body of evidence exists that the thymus produces regulatory T ce lls that suppress the response of other T cells to antigenic stimulation. W e report that TGF-beta can induce certain CD4(+) T cells in the naive (CD45 RA(+)RO(-)) fraction in human peripheral blood to develop powerful, contact -dependent suppressive activity that is not antagonized by anti-TGF-beta or anti-IL-10 mAbs. The costimulatory effects of TGF-beta on naive CD4(+) T c ells up-regulated CD25 and CTLA-4 expression, increased their transition to the activated phenotype, but decreased activation-induced apoptosis. Suppr essive activity was concentrated in the CD25(+) fraction. These CD4(+)CD25( +) regulatory cells prevented CD8(+) T cells from proliferating in response to alloantigens and from becoming cytotoxic effector cells. Moreover, thes e regulatory cells exerted their suppressive activities in remarkably low n umbers and maintained these effects even after they are expanded. Once acti vated, their suppressive properties were Ag nonspecific. Although <1% of na ive CD4(+) T cells expressed CD25, depletion of this subset before priming with TGF-beta markedly decreased the generation of suppressive activity. Th is finding suggests that CD4(+)CD25(+) regulatory T cells induced ex vivo a re the progeny of thymus-derived regulatory T cells bearing a similar pheno type. The adoptive transfer of these regulatory T cells generated and expan ded ex vivo has the potential to prevent rejection of allogeneic organ graf ts.