CD4+CD25+ T regulatory cells, immunotherapy of cancer, and interleukin-2.
CD4+CD25+ T regulatory (Treg) cells control immunologic tolerance to self-antigens and play a role in suppressing antitumor immune responses, but the mechanism of suppression in vivo remains uncertain. Recently, signaling through the high-affinity interleukin-2 (IL-2) receptor has been shown to be critical for Treg cell differentiation and survival in vivo. Mice deficient in IL-2 or its receptor (CD25 or CD122) or deficient in downstream signaling molecules, including JAK-3 and STAT-5, do not develop a stable population of Treg cells and subsequently acquire lymphoproliferative disease and autoimmunity. in vitro, IL-2 is required to expand Treg cells and to induce their suppressive characteristics. Conversely, IL-2-based regimens can activate cellular antitumor immunity and are the mainstay of immunotherapies directed against melanoma and kidney cancers. Given the seemingly disparate effects of IL-2, the authors discuss the possibility that IL-2 may not be the optimal T-cell growth factor in vivo, but rather an inducer of self-tolerance. The authors propose that other gamma c-signaling cytokines, including IL-15, may be alternative choices for the immunotherapy of cancer.
Antony
Paul Andrew
PA
Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Mark O. Hatfield Clinical Research Center, Bethesda, Maryland 20892, USA. Paul_Antony@nih.gov
Restifo
Nicholas P
NP
D019264:Adoptive Transfer; D000818:Animals; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000378:metabolism / Q000502:physiology*; D008232:Lymphoproliferative Disorders / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D010641:Phenotype; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000378:metabolism
D007376:Interleukin-2; D015375:Receptors, Interleukin-2
J Immunol. 1999 Nov 15;163(10):5211-8
10553041
J Immunol. 2000 Jan 1;164(1):183-90
10605010
Cancer J Sci Am. 2000 Feb;6 Suppl 1:S76-80
10685664
J Immunol. 2000 Apr 15;164(8):3982-9
10754288
Ann Rheum Dis. 2000 Nov;59 Suppl 1:i109-14
11053100
J Exp Med. 2000 Nov 6;192(9):1213-22
11067871
Annu Rev Immunol. 2001;19:565-94
11244047
Nature. 2001 May 17;411(6835):380-4
11357146
Crit Rev Immunol. 2000;20(6):433-50
11396680
Cancer Res. 2001 Jun 15;61(12):4766-72
11406550
Trends Immunol. 2001 Jul;22(7):394-400
11429324
J Immunol. 2001 Aug 1;167(3):1137-40
11466326
Nat Immunol. 2001 Sep;2(9):789-92
11526387
Nat Immunol. 2001 Sep;2(9):882-8
11526406
J Exp Med. 2001 Sep 17;194(6):823-32
11560997
J Biol Chem. 2001 Oct 5;276(40):37672-9
11483607
Ann N Y Acad Sci. 2001 Sep;941:166-76
11594570
Nat Med. 2001 Dec;7(12):1339-46
11726975
J Immunol. 2002 May 1;168(9):4272-6
11970966
J Immunol. 2002 Jun 15;168(12):5979-83
12055202
Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8832-7
12084927
Nature. 2002 Jun 27;417(6892):949-54
12068308
Nat Rev Immunol. 2002 Jun;2(6):389-400
12093005
J Exp Med. 2002 Jul 15;196(2):237-46
12119348
Nat Immunol. 2002 Aug;3(8):756-63
12089509
J Immunol. 2002 Sep 1;169(5):2756-61
12193750
Immunity. 2002 Aug;17(2):167-78
12196288
J Exp Med. 2002 Sep 16;196(6):851-7
12235217
J Immunol. 2002 Nov 1;169(9):4850-60
12391195
Science. 2002 Oct 25;298(5594):850-4
12242449
Nature. 2002 Dec 5;420(6915):502-7
12466842
J Immunother. 2003 Jan-Feb;26(1):85-93
12514432
Eur J Immunol. 2002 Nov;32(11):3267-75
12555672
Science. 2003 Feb 14;299(5609):1033-6
12532024
J Exp Med. 1999 Aug 2;190(3):355-66
10430624
J Exp Clin Cancer Res. 1999 Jun;18(2):225-32
10464712
Nat Rev Immunol. 2004 Nov;4(11):889-99
15516968
Nat Med. 2004 Dec;10(12):1390-6
15558056
J Immunol. 2004 Dec 15;173(12):7259-68
15585848
Trends Immunol. 2005 Feb;26(2):111-7
15668127
J Immunol. 2005 Mar 1;174(5):2591-601
15728465
Nat Rev Immunol. 2003 Mar;3(3):223-32
12658270
Nat Rev Immunol. 2003 Mar;3(3):253-7
12658273
Nat Immunol. 2003 Apr;4(4):330-6
12612578
J Immunol. 2003 Apr 15;170(8):3939-43
12682220
Nat Med. 2003 May;9(5):540-7
12692546
Cancer Immun. 2002 Feb 22;2:1
12747746
J Exp Med. 2003 Jul 21;198(2):235-47
12874257
Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8886-91
12857946
J Exp Med. 2003 Aug 18;198(4):569-80
12925674
Nat Rev Cancer. 2003 Sep;3(9):666-75
12951585
J Immunol. 2003 Oct 1;171(7):3435-41
14500638
J Immunol. 2003 Dec 1;171(11):5727-35
14634080
Nat Immunol. 2003 Dec;4(12):1206-12
14578884
J Exp Med. 2003 Dec 15;198(12):1875-86
14676299
J Immunol. 2004 Jan 15;172(2):834-42
14707053
J Immunol. 2004 Feb 1;172(3):1540-7
14734732
Immunity. 2004 Jan;20(1):107-18
14738769
Eur J Immunol. 2004 Feb;34(2):366-76
14768041
Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):1969-74
14762166
Blood. 2004 Mar 1;103(5):1755-62
14604957
J Immunol. 2004 Mar 1;172(5):3157-66
14978122
Immunol Cell Biol. 2004 Feb;82(1):84-90
14984599
Cancer Res. 2004 Mar 1;64(5):1595-9
14996715
Annu Rev Immunol. 2004;22:531-62
15032588
J Immunol. 2004 Apr 1;172(7):3983-8
15034008
J Immunol. 2004 Apr 1;172(7):4285-91
15034042
J Immunol. 2004 Apr 15;172(8):4686-90
15067043
J Immunol. 2004 May 1;172(9):5149-53
15100250
J Immunol. 2004 May 1;172(9):5287-96
15100267
J Immunol. 2004 May 1;172(9):5420-6
15100283
Nat Immunol. 2004 May;5(5):508-15
15064759
Immunology. 2004 Jun;112(2):177-82
15147560
J Immunol. 2004 Jun 1;172(11):6519-23
15153463
J Exp Med. 2004 Jun 21;199(12):1725-30
15210748
J Exp Med. 2004 Jul 5;200(1):89-98
15238608
Nat Rev Immunol. 2004 Aug;4(8):595-602
15286726
Eur J Immunol. 2004 Sep;34(9):2480-8
15307180
Immunity. 2004 Aug;21(2):267-77
15308106
J Immunol. 2004 Sep 1;173(5):3131-9
15322173
Nat Med. 2004 Sep;10(9):942-9
15322536
Nat Med. 2004 Sep;10(9):909-15
15340416
Nat Rev Immunol. 2004 Sep;4(9):665-74
15343366
J Immunol. 2004 Nov 1;173(9):5415-24
15494488
Science. 1976 Sep 10;193(4257):1007-8
181845
J Exp Med. 1980 Jan 1;151(1):69-80
6444236
J Exp Med. 1982 Apr 1;155(4):1063-74
6460831
Cancer Immunol Immunother. 1984;16(3):175-81
6231095
J Leukoc Biol. 1984 Jul;36(1):27-37
6234371
Science. 1984 Sep 28;225(4669):1487-9
6332379
Cancer Immunol Immunother. 1984;18(2):69-74
6334549
Proc Natl Acad Sci U S A. 1985 Jun;82(12):4230-4
2987968
N Engl J Med. 1985 Dec 5;313(23):1485-92
3903508
J Exp Med. 1986 Nov 1;164(5):1652-66
2945892
J Immunol Methods. 1987 Aug 24;102(1):127-41
3305708
Cancer Res. 1989 Apr 1;49(7):1649-54
2522344
J Natl Cancer Inst. 1994 Aug 3;86(15):1159-66
8028037
J Immunol. 1995 Aug 1;155(3):1151-64
7636184
J Exp Med. 1995 Dec 1;182(6):1769-76
7500021
J Exp Med. 1996 Aug 1;184(2):387-96
8760792
J Immunol. 1996 Dec 1;157(11):4762-70
8943377
Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3168-71
9096364
J Immunol. 1998 Feb 1;160(3):1212-8
9570536
J Immunol. 1998 Nov 15;161(10):5313-20
9820504
Blood. 1999 Mar 1;93(5):1634-42
10029592