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

Abstract

CD4(+)CD25(+) regulatory T (T(reg)) cells have a crucial role in maintaining immune tolerance. Mice and humans born lacking T(reg) cells develop severe autoimmune disease, and depletion of T(reg) cells in lymphopenic mice induces autoimmunity. Interleukin (IL)-2 signaling is required for thymic development, peripheral expansion and suppressive activity of T(reg) cells. Animals lacking IL-2 die of autoimmunity, which is prevented by administration of IL-2-responsive T(reg) cells. In light of the emerging evidence that one of the primary physiologic roles of IL-2 is to generate and maintain T(reg) cells, the question arises as to the effects of IL-2 therapy on them. We monitored T(reg) 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 T(reg) cells present in normal hosts. These studies suggest that IL-2 and lymphopenia are primary modulators of CD4(+)CD25(+) T(reg) cell homeostasis.

• Authors: Hua Zhang, Kevin S Chua, Martin Guimond, Veena Kapoor, Margaret V Brown, Thomas A Fleisher, Lauren M Long, Donna Bernstein, Brenna J Hill, Daniel C Douek, Jay A Berzofsky, Charles S Carter, E J Read, Lee J Helman, Crystal L Mackall
• Journal: Nature medicine (Nat Med) Vol. 11 Issue 11 Pg. 1238-43 (Nov 2005) ISSN: 1078-8956 [Print] United States
• PMID: 16227988 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Interleukin-2
• Receptors, Interleukin-2
• Recombinant Proteins

Topics

• Adolescent
• Adult
• Animals
• CD4-Positive T-Lymphocytes (drug effects, immunology)
• Child
• Female
• Forkhead Transcription Factors (analysis)
• Homeostasis (immunology)
• Humans
• Interleukin-2 (administration & dosage, immunology, therapeutic use)
• Lymphocyte Transfusion
• Lymphopenia (chemically induced, drug therapy, immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Receptors, Interleukin-2 (immunology, metabolism)
• Recombinant Proteins (therapeutic use)
• Sarcoma (complications, drug therapy)
• T-Lymphocytes, Regulatory (drug effects, immunology)