title: 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.affiliation: Pediatric Oncology Branch, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Chua
authors.forename: Martin
authors.initials: M
authors.lastname: Guimond
authors.forename: Veena
authors.initials: V
authors.lastname: Kapoor
authors.forename: Margaret V
authors.initials: MV
authors.lastname: Brown
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fleisher
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Long
authors.forename: Donna
authors.initials: D
authors.lastname: Bernstein
authors.forename: Brenna J
authors.initials: BJ
authors.lastname: Hill
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Jay A
authors.initials: JA
authors.lastname: Berzofsky
authors.forename: Charles S
authors.initials: CS
authors.lastname: Carter
authors.forename: E J
authors.initials: EJ
authors.lastname: Read
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Helman
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Mackall
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002648:Child; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D017710:Lymphocyte Transfusion; D008231:Lymphopenia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D015375:Receptors, Interleukin-2 / Q000276:immunology* / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D012509:Sarcoma / Q000150:complications / Q000188:drug therapy; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins