title: Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection.
abstract: 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.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON, Canada. brad.jones@utoronto.ca
authors.forename: R Brad
authors.initials: RB
authors.lastname: Jones
authors.forename: Lishomwa C
authors.initials: LC
authors.lastname: Ndhlovu
authors.forename: Jason D
authors.initials: JD
authors.lastname: Barbour
authors.forename: Prameet M
authors.initials: PM
authors.lastname: Sheth
authors.forename: Aashish R
authors.initials: AR
authors.lastname: Jha
authors.forename: Brian R
authors.initials: BR
authors.lastname: Long
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Wong
authors.forename: Malathy
authors.initials: M
authors.lastname: Satkunarajah
authors.forename: Marc
authors.initials: M
authors.lastname: Schweneker
authors.forename: Joan M
authors.initials: JM
authors.lastname: Chapman
authors.forename: Gabor
authors.initials: G
authors.lastname: Gyenes
authors.forename: Bahareh
authors.initials: B
authors.lastname: Vali
authors.forename: Martin D
authors.initials: MD
authors.lastname: Hyrcza
authors.forename: Feng Yun
authors.initials: FY
authors.lastname: Yue
authors.forename: Colin
authors.initials: C
authors.lastname: Kovacs
authors.forename: Aref
authors.initials: A
authors.lastname: Sassi
authors.forename: Mona
authors.initials: M
authors.lastname: Loutfy
authors.forename: Roberta
authors.initials: R
authors.lastname: Halpenny
authors.forename: Desmond
authors.initials: D
authors.lastname: Persad
authors.forename: Gerald
authors.initials: G
authors.lastname: Spotts
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Hecht
authors.forename: Tae-Wook
authors.initials: TW
authors.lastname: Chun
authors.forename: Joseph M
authors.initials: JM
authors.lastname: McCune
authors.forename: Rupert
authors.initials: R
authors.lastname: Kaul
authors.forename: James M
authors.initials: JM
authors.lastname: Rini
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Nixon
authors.forename: Mario A
authors.initials: MA
authors.lastname: Ostrowski
mesh_terms: 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
chemical_list: 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