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 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.
Zhang
Hua
H
Pediatric Oncology Branch, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
Chua
Kevin S
KS
Guimond
Martin
M
Kapoor
Veena
V
Brown
Margaret V
MV
Fleisher
Thomas A
TA
Long
Lauren M
LM
Bernstein
Donna
D
Hill
Brenna J
BJ
Douek
Daniel C
DC
Berzofsky
Jay A
JA
Carter
Charles S
CS
Read
E J
EJ
Helman
Lee J
LJ
Mackall
Crystal L
CL
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
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins