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

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Abstract
CD4+CD25+ regulatory T (Treg) cells have a crucial role in maintaining immune tolerance. Mice and humans born lacking Treg cells develop severe autoimmune disease1,2, and depletion of Treg cells in lymphopenic mice induces autoimmunity3,4. Interleukin (IL)-2 signaling is required for thymic development5, peripheral expansion6 and suppressive activity of Treg cells7. Animals lacking IL-2 die of autoimmunity8,9, which is prevented by administration of IL-2–responsive Treg cells5. In light of the emerging evidence that one of the primary physiologic roles of IL-2 is to generate and maintain Treg cells10, 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+CD25hi cells underwent homeostatic peripheral expansion during immune reconstitution, and in lymphopenic individuals receiving IL-2, the Treg cell compartment was markedly increased. Mouse studies showed that IL-2 therapy induced expansion of existent Treg cells in normal hosts, and IL-2–induced Treg cell expansion was further augmented by lymphopenia. On a per-cell basis, Treg 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+ Treg cell homeostasis.