Ontogeny, function, and peripheral homeostasis of regulatory T cells in the absence of interleukin-7

Mice lacking interleukin-7 (IL-7(-/-) mice) have no signs of autoimmune disease, contrary to other models of lymphopenia. We investigated whether the absence of disease was due to the fact that IL-7 is dispensable for the ontogeny, function, and homeostasis of regulatory CD4(+) T cells. We show here that the establishment of the peripheral pool of Foxp3-expressing regulatory cells is IL-7 independent, and the premature involution of the thymus in IL-7(-/-) mice does not change the representation of the CD4(+)CD25(+) T-cell compartment. In addition, CD4(+)CD25(+) T cells expand in the absence of IL-7, without losing Foxp3 expression. The frequency of activated peripheral CD4(+) T cells increases with age in both the CD25(-) and CD25(+) compartments, with the CD4(+)CD25(+) T cells displaying signs of constant activation. IL-7(-/-) CD4(+)CD25(+) T cells control inflammatory bowel disease induced by IL-7(-/-) T cells even in hosts lacking IL-7. Depletion of the CD25(+) T-cell subset after thymic involution results in a mild form of inflammatory bowel disease (IBD), which resolves concomitantly with the regeneration of this subset. This study shows for the first time that IL-7(-/-) mice have a robust regulatory Foxp3-expressing CD4(+) T-cell compartment that controls T-cell-mediated disease. It also highlights the potential of the regulatory Foxp3-expressing CD4(+)CD25(-) T-cell population to restore a functional CD4(+)CD25(+) T-cell compartment through an IL-7-independent pathway.