Forkhead box P3 (FOXP3)(+) regulatory T (T(Reg)) cells are potent mediators of dominant self tolerance in the periphery. But confusion as to the identity, stability and suppressive function of human T(Reg) cells has, to date, impeded the general therapeutic use of these cells. Recent studies have suggested that human T(Reg) cells are functionally and phenotypically diverse. Here we discuss recent findings regarding human T(Reg) cells, including the ontogeny and development of T(Reg) cell subsets that have naive or memory phenotypes, the unique mechanisms of suppression mediated by T(Reg) cell subsets and factors that regulate T(Reg) cell lineage commitment. We discuss future studies that are needed for the successful therapeutic use of human T(Reg) cells.

IntroductionRegulatory T cells (Tregs), characterized by high expression of FoxP3, are potent immunomodulators of T-cell activation that suppress proliferation and cytokine secretion by effector T cells. [1][2][3][4][5] Loss of Tregs by either gene deletion of FoxP3 in mice or mutations in humans results in autoimmune disease and the inability to effectively regulate T-cell activation. 6,7 While Tregs play a fundamental role in protection of autoimmunity, their differentiation is tightly linked to the development of IL-17-producing (Th17) cells, a highly pathogenic effector T-cell subset involved in inducing inflammation and autoimmune tissue injury. 8,9 Both loss of Treg function and induction of Th17 cells have been implicated in the pathogenesis of human autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, Crohn disease, and psoriasis. [10][11][12][13][14] Although Tregs appear to be central in regulating immune responses to self-antigens, mechanisms must be present to rapidly block their suppressive activity and enable immune activation during an acute microbial infection. In such circumstances, antigen-presenting cells (APC) secrete inflammatory cytokines, such as interleukin-1␤ (IL-1␤) and IL-6, which induce the potent effector responses necessary to clear the infection. In this regard, our data and the work of others have demonstrated that IL-1␤ and IL-6 can drive memory CD4 ϩ T cells to secrete 16 , which has been shown to abrogate suppression by Treg cells, 17 also drives Th17 differentiation in naive cells when paired with transforming growth factor ␤ (TGF␤) in mouse 18 or with IL-1␤, interleukin-23 (IL-23), and TGF␤ in human, 19 although the minimal requirements for Th17 differentiation in human are still being defined. 15,[20][21][22] The role of TGF␤ in Th17 development is surprising, given that TGF␤ promotes adaptive Treg differentiation in murine models and enhances FoxP3 expression in the human system. 23 Yet recent studies in mouse have indicated that TGF␤ and IL-6 can induce IL-17 production in Tregs. 24,25 Despite the apparent duality in Treg/Th17 function, it is becoming increasingly clear that these cell subsets share common cytokine signaling pathways.The memory CD4 ϩ CD25 high human Treg lineage can be subdivided into 2 functionally distinct subsets classified by expression of the major histocompatibility complex (MHC) class II dimer human leukocyte antigen-DR (HLA-DR). 26 DR ϩ Tregs do not enter into cell cycle with T-cell receptor (TCR) cross-linking and exhibit immediate contact-dependent suppressor function. In contrast, DR Ϫ Tregs can enter into cell cycle after activation, secrete the inhibitory cytokine interleukin-10 (IL-10) but not the effector cytokine interferon-␥ (IFN␥), and demonstrate delayed kinetics of suppression, requiring 4 to 5 days for maximal inhibition of proliferation of responder CD4 ϩ T cells. 26 We have previously reported that, in cocultures of human Tregs and responder T cells (Tresp) provided with strong TCR stimulation, the Tresp are refrac...

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