TIM-3 is expressed on activated human CD4+ T cells and regulates Th1 and Th17 cytokines.
TIM-3 is a molecule selectively expressed on a subset of murine IFN-gamma-secreting T helper 1 (Th1) cells but not Th2 cells, and regulates Th1 immunity and tolerance in vivo. At this time little is known about the role of TIM-3 on human T cells. To determine if TIM-3 similarly identifies and regulates Th1 cells in humans, we generated a panel of mAb specific for human TIM-3. We report that TIM-3 is expressed by a subset of activated CD4(+) cells, and that anti-CD3/anti-CD28 stimulation increases both the level of expression as well as the number of TIM-3(+) T cells. We also find that TIM-3 is expressed at high levels on in vitro polarized Th1 cells, and is expressed at lower levels on Th17 cells. In addition, human CD4(+) T cells secreted elevated levels of IFN-gamma, IL-17, IL-2, and IL-6, but not IL-10, IL-4, or TNF-alpha, when stimulated with anti-CD3/anti-CD28 in the presence of TIM-3-specific, putative antagonistic antibodies. This was not mediated by differences in proliferation or cell death, but rather by induction of cytokines at the transcriptional level. These results suggest that TIM-3 is a negative regulator of human T cells and regulates Th1 and Th17 cytokine secretion.
Hastings
William D
WD
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Anderson
David E
DE
Kassam
Nasim
N
Koguchi
Ken
K
Greenfield
Edward A
EA
Kent
Sally C
SC
Zheng
Xin Xiao
XX
Strom
Terry B
TB
Hafler
David A
DA
Kuchroo
Vijay K
VK
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects / Q000276:immunology; D037161:Galectins / Q000276:immunology / Q000378:metabolism; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D016207:Cytokines; D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D007155:Immunologic Factors; C105032:LGALS9 protein, human; D008565:Membrane Proteins
Nature. 2006 May 11;441(7090):235-8
16648838
Trends Immunol. 2001 Sep;22(9):481-2
11556323
Science. 2007 Nov 16;318(5853):1141-3
18006747
Nature. 2008 Jul 17;454(7202):350-2
18469800
J Immunol. 1986 Apr 1;136(7):2348-57
2419430
Nat Immunol. 2005 Dec;6(12):1245-52
16286920
J Invest Dermatol. 1994 Jun;102(6):828-32
8006444
Nature. 2008 Jun 19;453(7198):1051-7
18563156
Nature. 2002 Jan 31;415(6871):536-41
11823861
Nat Immunol. 2003 Nov;4(11):1102-10
14556006
J Exp Med. 2006 Jun 12;203(6):1413-8
16754722
J Immunol. 2008 Apr 1;180(7):4409-14
18354161
J Immunol. 2008 Dec 1;181(11):7660-9
19017954
Blood. 2007 Oct 1;110(7):2565-8
17620455
J Immunol. 1999 Feb 1;162(3):1246-51
9973376
Immunol Today. 1997 Aug;18(8):387-92
9267081
Nat Immunol. 2008 Jun;9(6):650-7
18454150
J Exp Med. 2007 Aug 6;204(8):1849-61
17635957
Nat Rev Immunol. 2005 Mar;5(3):251-60
15738955
Nat Immunol. 2008 Jun;9(6):641-9
18454151
J Exp Med. 2008 Jul 7;205(7):1543-50
18591412
Int J Cancer. 1994 Aug 1;58(3):317-23
7914181
J Immunol. 2001 Sep 1;167(5):2972-8
11509647
J Immunol. 1999 Jan 1;162(1):494-502
9886425
J Allergy Clin Immunol. 1997 Jul;100(1):1-6
9257779
Nat Immunol. 2003 Nov;4(11):1093-101
14556005
Methods Mol Biol. 2000;138:231-42
10840763
Science. 1991 Oct 11;254(5029):279-82
1681588
J Exp Med. 2008 Nov 24;205(12):2763-79
19001139