Interleukin-2-dependent mechanisms of tolerance and immunity in vivo.
IL-2 is a critical T cell growth factor in vitro, but predominantly mediates tolerance in vivo. IL-2 is mainly produced by CD4(+) Th cells, but the role of Th cell-derived IL-2 in vivo is controversial. We demonstrate that during immunity to a tumor/self-Ag, the predominant role of Th cell-derived IL-2 was to maintain IL-2Ralpha (CD25) on CD4(+) T regulatory cells (T(reg)), which resulted in their maintenance of the T(reg) cell lineage factor, Forkhead/winged helix transcription factor (Foxp3), and tolerance. However, in the absence of T(reg) cells, Th cell-derived IL-2 maintained effector T cells and caused autoimmunity. IL-2R signaling was indispensable for T(reg) cell homeostasis and efficient suppressor function in vivo, but, surprisingly, was not required for their generation, because IL-2(-/-) and CD25(-/-) mice both contained Foxp3(+) T cells in the periphery. IL-2R signaling was also important for CD8(+) T cell immunity, because CD25(-/-) tumor-reactive CD8(+) T cells failed to affect established tumors. Conversely, IL-2R signaling was not required for Th cell function. Lastly, administration of anti-IL-2 plus exogenous IL-15 to tumor-bearing mice enhanced the adoptive immunotherapy of cancer. Therefore, Th cell-derived IL-2 paradoxically controls both tolerance and immunity to a tumor/self-Ag in vivo.
Antony
Paul A
PA
Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. paul_antony@mac.com
Paulos
Chrystal M
CM
Ahmadzadeh
Mojgan
M
Akpinarli
Akgül
A
Palmer
Douglas C
DC
Sato
Noriko
N
Kaiser
Andrew
A
Hinrichs
Christian S
CS
Heinrichs
Christian
C
Klebanoff
Christopher A
CA
Tagaya
Yutaka
Y
Restifo
Nicholas P
NP
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001324:Autoantigens / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000906:Antibodies; D001324:Autoantigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D007371:Interferon-gamma