CD4+CD25lowGITR+ cells: A novel human CD4+ T-cell population with regulatory activity

Treg subsets play a role in sustaining peripheral tolerance, are characterized by markers such as forkhead winged-helix transcription factor (FOXP3) and CD25, and produce suppressive cytokines, such as IL-10 and TGF-beta. Glucocorticoid-induced TNF receptor family-related (GITR) protein has been suggested to regulate Treg activity in mice. The aim of our study was to investigate GITR expression in human CD4(+) T lymphocytes and its possible role in Treg function. Results indicate that a subset of CD4(+) T cells in the peripheral blood expresses GITR and low levels of CD25 (CD4(+)CD25(low)GITR(+)). These cells show Treg features as they express FOXP3, IL-10, TGF-beta and are anergic but, as opposed to natural Tregs, express low levels of CTLA-4 and are CD127(high). CD4(+)CD25(low)GITR(+) cells represent a low percentage of the CD4(+) T-cell population (0.32-1.74%) and are mostly memory cells. Functional experiments demonstrated that CD4(+)CD25(low)GITR(+) cells have relevant suppressive activity that depends on TGF-beta. Moreover, an anti-GITR Ab inhibited their suppressive activity, as observed in CD4(+) CD25(+) murine Tregs. Taken together, these data indicate that human CD4(+)CD25(low)GITR(+) cells represent a distinct Treg subpopulation.