Phenotypic and functional differences between human CD4 +CD25+ and type 1 regulatory T cells

T regulatory (Tr) cells have an essential role in the induction and maintenance of tolerance to both and foreign self-antigens. Many types of T cells with regulatory activity have been described in mice and humans, and those within the CD4⁺ subset have been extensively characterized. CD4 ⁺ Type-1 regulatory T (Tr1) cells produce high levels of IL-10 and mediate IL-10-dependent suppression, whereas the effects of naturally occurring CD4⁺CD25⁺ Tr cells appear to be cell-contact-dependent. Tr1 cells arise in the periphery upon encountering antigen in a tolerogenic environment. In contrast, it appears that CD4⁺CD25⁺ Tr cells can either arise directly in the thymus or be induced by antigen in the periphery. We have been interested in defining the phenotype and function of different subsets of CD4⁺ Tr cells present in human peripheral blood, with the ultimate aim of designing therapeutic strategies to harness their immunoregulatory effects. This review will discuss the similarities and differences between human Tr1 and naturally occurring CD4⁺CD25 ⁺ Tr cells, as well as evidence that indicates that they have nonoverlapping, but synergistic roles in immune homeostasis.