Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection.
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-specific T cells. Thus, Tim-3 represents a novel target for the therapeutic reversal of HIV-1-associated T cell dysfunction.
Jones
R Brad
RB
Department of Immunology, University of Toronto, Toronto, ON, Canada. brad.jones@utoronto.ca
Ndhlovu
Lishomwa C
LC
Barbour
Jason D
JD
Sheth
Prameet M
PM
Jha
Aashish R
AR
Long
Brian R
BR
Wong
Jessica C
JC
Satkunarajah
Malathy
M
Schweneker
Marc
M
Chapman
Joan M
JM
Gyenes
Gabor
G
Vali
Bahareh
B
Hyrcza
Martin D
MD
Yue
Feng Yun
FY
Kovacs
Colin
C
Sassi
Aref
A
Loutfy
Mona
M
Halpenny
Roberta
R
Persad
Desmond
D
Spotts
Gerald
G
Hecht
Frederick M
FM
Chun
Tae-Wook
TW
McCune
Joseph M
JM
Kaul
Rupert
R
Rini
James M
JM
Nixon
Douglas F
DF
Ostrowski
Mario A
MA
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D023241:Antiretroviral Therapy, Highly Active; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity; D006680:HLA Antigens; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology; D000098815:T-bet Transcription Factor
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D050990:GATA3 Transcription Factor; C448908:HAVCR2 protein, human; D006680:HLA Antigens; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D050799:STAT5 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases