Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+ CD25+ regulatory T cells

CD4(+)CD25(+) regulatory T ( T-reg) cells have a crucial role in maintaining immune tolerance. Mice and humans born lacking Treg cells develop severe autoimmune disease(1,2), and depletion of Treg cells in lymphopenic mice induces autoimmunity(3,4). Interleukin ( IL)-2 signaling is required for thymic development(5), peripheral expansion(6) and suppressive activity of T(reg)cells(7). Animals lacking IL-2 die of autoimmunity(8,9), which is prevented by administration of IL-2-responsive T(reg)cells(5). In light of the emerging evidence that one of the primary physiologic roles of IL-2 is to generate and maintain T-reg cells(10), the question arises as to the effects of IL-2 therapy on them. We monitored Treg cells during immune reconstitution in individuals with cancer who did or did not receive IL-2 therapy. CD4(+)CD25(hi) cells underwent homeostatic peripheral expansion during immune reconstitution, and in lymphopenic individuals receiving IL-2, the T-reg cell compartment was markedly increased. Mouse studies showed that IL-2 therapy induced expansion of existent T-reg cells in normal hosts, and IL-2 induced T-reg cell expansion was further augmented by lymphopenia. On a per-cell basis, T-reg cells generated by IL-2 therapy expressed similar levels of FOXP3 and had similar potency for suppression compared to Treg cells present in normal hosts. These studies suggest that IL-2 and lymphopenia are primary modulators of CD4(+)CD25(+) T-reg cell homeostasis.