Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection

被引：612

作者：

Jones, R. Brad ^{[1
]}

Ndhlovu, Lishomwa C. ^{[5
]}

Barbour, Jason D. ^{[6
]}

Sheth, Prameet M. ^{[2
]}

Jha, Aashish R. ^{[5
]}

Long, Brian R. ^{[5
]}

Wong, Jessica C. ^{[1
]}

Satkunarajah, Malathy ^{[3
]}

Schweneker, Marc ^{[5
]}

Chapman, Joan M. ^{[5
]}

Gyenes, Gabor ^{[1
]}

Vali, Bahareh ^{[2
]}

Hyrcza, Martin D. ^{[2
]}

Yue, Feng Yun ^{[1
]}

Kovacs, Colin ^{[4
]}

Sassi, Aref ^{[8
]}

Loutfy, Mona ^{[7
]}

Halpenny, Roberta ^{[7
]}

Persad, Desmond ^{[8
]}

Spotts, Gerald ^{[6
]}

Hecht, Frederick M. ^{[6
]}

Chun, Tae-Wook ^{[9
]}

McCune, Joseph M. ^{[5
]}

Kaul, Rupert ^{[2
]}

Rini, James M. ^{[3
]}

Nixon, Douglas F. ^{[5
]}

Ostrowski, Mario A. ^{[1
,2
,10
]}

机构：

[1] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada

[2] Univ Toronto, Div Clin Sci, Toronto, ON M5S 1A8, Canada

[3] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada

[4] Univ Toronto, Dept Med, Toronto, ON M5S 1A8, Canada

[5] Univ Calif San Francisco, Div Expt Med, San Francisco, CA 94110 USA

[6] Univ Calif San Francisco, Div HIV AIDS, Dept Med, San Francisco Gen Hosp, San Francisco, CA 94110 USA

[7] Canadian Immunodeficiency Res Collaborat, Toronto, ON M5B 1L6, Canada

[8] Maple Leaf Med Clin, Toronto, ON M5B 1L6, Canada

[9] NIAID, NIH, Bethesda, MD 20892 USA

[10] St Michaels Hosp, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2008年 / 205卷 / 12期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1084/jem.20081398

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Progressive loss of T cell functionality is a hallmark of chronic infection with human immunodeficiency virus 1 (HIV-1). We have identified a novel population of dysfunctional T cells marked by surface expression of the glycoprotein Tim-3. The frequency of this population was increased in HIV-1-infected individuals to a mean of 49.4 +/- SD 12.9% of CD8(+) T cells expressing Tim-3 in HIV-1-infected chronic progressors versus 28.5 +/- 6.8% in HIV-1-uninfected individuals. Levels of Tim-3 expression on T cells from HIV-1-infected inviduals correlated positively with HIV-1 viral load and CD38 expression and inversely with CD4(+) T cell count. In progressive HIV-1 infection, Tim-3 expression was up-regulated on HIV-1 specific CD8(+) T cells. Tim-3-expressing T cells failed to produce cytokine or proliferate in response to antigen and exhibited impaired Stat5, Erk1/2, and p38 signaling. Blocking the Tim-3 signaling pathway restored proliferation and enhanced cytokine production in HIV-1-specifi c T cells. Thus, Tim-3 represents a novel target for the therapeutic reversal of HIV-1-associated T cell dysfunction.

引用

页码：2763 / 2779

页数：17

共 53 条

[51] Lack of TIM-3 immunoregulation in multiple sclerosis
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