Expansion of dysfunctional Tim-3 - Expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques

Tsuyoshi Fujita, Benjamin Burwitz, Glen M. Chew, Jason S. Reed, Reesab Pathak, Elizabeth Seger, Kiera L. Clayton, James M. Rini, Mario A. Ostrowski, Naoto Ishii, Marcelo J. Kuroda, Scott Hansen, Jonah Sacha, Lishomwa C. Ndhlovu

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The T cell Ig- and mucin domain-containing molecule-3 (Tim-3) negative immune checkpoint receptor demarcates functionally exhausted CD8+ T cells arising from chronic stimulation in viral infections like HIV. Tim-3 blockade leads to improved antiviral CD8+ T cell responses in vitro, therefore, represents a novel intervention strategy to restore T cell function in vivo and protect from disease progression. However, the Tim-3 pathway in the physiologically relevant rhesus macaque SIV model of AIDS remains uncharacterized. We report that Tim-3+CD8+ T cell frequencies are significantly increased in lymph nodes, but not in peripheral blood, in SIV-infected animals. Tim-3+PD-1+CD8+ T cells are similarly increased during SIV infection and positively correlate with SIV plasma viremia. Tim-3 expression was found primarily on effector memory CD8+ T cells in all tissues examined. Tim-3+CD8+ T cells have lower Ki-67 content and minimal cytokine responses to SIV compared with Tim-3-CD8+ T cells. During acute-phase SIV replication, Tim-3 expression peaked on SIV-specific CD8+ T cells by 2 wk postinfection and then rapidly diminished, irrespective of mutational escape of cognate Ag, suggesting non-TCR-driven mechanisms for Tim-3 expression. Thus, rhesus Tim-3 in SIV infection partially mimics human Tim-3 in HIV infection and may serve as a novel model for targeted studies focused on rejuvenating HIV-specific CD8+ T cell responses.

Original languageEnglish (US)
Pages (from-to)5576-5583
Number of pages8
JournalJournal of Immunology
Volume193
Issue number11
DOIs
StatePublished - Dec 1 2014

Fingerprint

Simian Immunodeficiency Virus
Virus Diseases
Macaca mulatta
T-Lymphocytes
HIV
Viremia
Mucins
Infection
HIV Infections
Antiviral Agents
Disease Progression
Acquired Immunodeficiency Syndrome
Lymph Nodes

ASJC Scopus subject areas

  • Immunology

Cite this

Expansion of dysfunctional Tim-3 - Expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques. / Fujita, Tsuyoshi; Burwitz, Benjamin; Chew, Glen M.; Reed, Jason S.; Pathak, Reesab; Seger, Elizabeth; Clayton, Kiera L.; Rini, James M.; Ostrowski, Mario A.; Ishii, Naoto; Kuroda, Marcelo J.; Hansen, Scott; Sacha, Jonah; Ndhlovu, Lishomwa C.

In: Journal of Immunology, Vol. 193, No. 11, 01.12.2014, p. 5576-5583.

Research output: Contribution to journalArticle

Fujita, T, Burwitz, B, Chew, GM, Reed, JS, Pathak, R, Seger, E, Clayton, KL, Rini, JM, Ostrowski, MA, Ishii, N, Kuroda, MJ, Hansen, S, Sacha, J & Ndhlovu, LC 2014, 'Expansion of dysfunctional Tim-3 - Expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques', Journal of Immunology, vol. 193, no. 11, pp. 5576-5583. https://doi.org/10.4049/jimmunol.1400961
Fujita, Tsuyoshi ; Burwitz, Benjamin ; Chew, Glen M. ; Reed, Jason S. ; Pathak, Reesab ; Seger, Elizabeth ; Clayton, Kiera L. ; Rini, James M. ; Ostrowski, Mario A. ; Ishii, Naoto ; Kuroda, Marcelo J. ; Hansen, Scott ; Sacha, Jonah ; Ndhlovu, Lishomwa C. / Expansion of dysfunctional Tim-3 - Expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques. In: Journal of Immunology. 2014 ; Vol. 193, No. 11. pp. 5576-5583.
@article{e2100e7dbff9449fba6356711d38e7bc,
title = "Expansion of dysfunctional Tim-3 - Expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques",
abstract = "The T cell Ig- and mucin domain-containing molecule-3 (Tim-3) negative immune checkpoint receptor demarcates functionally exhausted CD8+ T cells arising from chronic stimulation in viral infections like HIV. Tim-3 blockade leads to improved antiviral CD8+ T cell responses in vitro, therefore, represents a novel intervention strategy to restore T cell function in vivo and protect from disease progression. However, the Tim-3 pathway in the physiologically relevant rhesus macaque SIV model of AIDS remains uncharacterized. We report that Tim-3+CD8+ T cell frequencies are significantly increased in lymph nodes, but not in peripheral blood, in SIV-infected animals. Tim-3+PD-1+CD8+ T cells are similarly increased during SIV infection and positively correlate with SIV plasma viremia. Tim-3 expression was found primarily on effector memory CD8+ T cells in all tissues examined. Tim-3+CD8+ T cells have lower Ki-67 content and minimal cytokine responses to SIV compared with Tim-3-CD8+ T cells. During acute-phase SIV replication, Tim-3 expression peaked on SIV-specific CD8+ T cells by 2 wk postinfection and then rapidly diminished, irrespective of mutational escape of cognate Ag, suggesting non-TCR-driven mechanisms for Tim-3 expression. Thus, rhesus Tim-3 in SIV infection partially mimics human Tim-3 in HIV infection and may serve as a novel model for targeted studies focused on rejuvenating HIV-specific CD8+ T cell responses.",
author = "Tsuyoshi Fujita and Benjamin Burwitz and Chew, {Glen M.} and Reed, {Jason S.} and Reesab Pathak and Elizabeth Seger and Clayton, {Kiera L.} and Rini, {James M.} and Ostrowski, {Mario A.} and Naoto Ishii and Kuroda, {Marcelo J.} and Scott Hansen and Jonah Sacha and Ndhlovu, {Lishomwa C.}",
year = "2014",
month = "12",
day = "1",
doi = "10.4049/jimmunol.1400961",
language = "English (US)",
volume = "193",
pages = "5576--5583",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "11",

}

TY - JOUR

T1 - Expansion of dysfunctional Tim-3 - Expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques

AU - Fujita, Tsuyoshi

AU - Burwitz, Benjamin

AU - Chew, Glen M.

AU - Reed, Jason S.

AU - Pathak, Reesab

AU - Seger, Elizabeth

AU - Clayton, Kiera L.

AU - Rini, James M.

AU - Ostrowski, Mario A.

AU - Ishii, Naoto

AU - Kuroda, Marcelo J.

AU - Hansen, Scott

AU - Sacha, Jonah

AU - Ndhlovu, Lishomwa C.

PY - 2014/12/1

Y1 - 2014/12/1

N2 - The T cell Ig- and mucin domain-containing molecule-3 (Tim-3) negative immune checkpoint receptor demarcates functionally exhausted CD8+ T cells arising from chronic stimulation in viral infections like HIV. Tim-3 blockade leads to improved antiviral CD8+ T cell responses in vitro, therefore, represents a novel intervention strategy to restore T cell function in vivo and protect from disease progression. However, the Tim-3 pathway in the physiologically relevant rhesus macaque SIV model of AIDS remains uncharacterized. We report that Tim-3+CD8+ T cell frequencies are significantly increased in lymph nodes, but not in peripheral blood, in SIV-infected animals. Tim-3+PD-1+CD8+ T cells are similarly increased during SIV infection and positively correlate with SIV plasma viremia. Tim-3 expression was found primarily on effector memory CD8+ T cells in all tissues examined. Tim-3+CD8+ T cells have lower Ki-67 content and minimal cytokine responses to SIV compared with Tim-3-CD8+ T cells. During acute-phase SIV replication, Tim-3 expression peaked on SIV-specific CD8+ T cells by 2 wk postinfection and then rapidly diminished, irrespective of mutational escape of cognate Ag, suggesting non-TCR-driven mechanisms for Tim-3 expression. Thus, rhesus Tim-3 in SIV infection partially mimics human Tim-3 in HIV infection and may serve as a novel model for targeted studies focused on rejuvenating HIV-specific CD8+ T cell responses.

AB - The T cell Ig- and mucin domain-containing molecule-3 (Tim-3) negative immune checkpoint receptor demarcates functionally exhausted CD8+ T cells arising from chronic stimulation in viral infections like HIV. Tim-3 blockade leads to improved antiviral CD8+ T cell responses in vitro, therefore, represents a novel intervention strategy to restore T cell function in vivo and protect from disease progression. However, the Tim-3 pathway in the physiologically relevant rhesus macaque SIV model of AIDS remains uncharacterized. We report that Tim-3+CD8+ T cell frequencies are significantly increased in lymph nodes, but not in peripheral blood, in SIV-infected animals. Tim-3+PD-1+CD8+ T cells are similarly increased during SIV infection and positively correlate with SIV plasma viremia. Tim-3 expression was found primarily on effector memory CD8+ T cells in all tissues examined. Tim-3+CD8+ T cells have lower Ki-67 content and minimal cytokine responses to SIV compared with Tim-3-CD8+ T cells. During acute-phase SIV replication, Tim-3 expression peaked on SIV-specific CD8+ T cells by 2 wk postinfection and then rapidly diminished, irrespective of mutational escape of cognate Ag, suggesting non-TCR-driven mechanisms for Tim-3 expression. Thus, rhesus Tim-3 in SIV infection partially mimics human Tim-3 in HIV infection and may serve as a novel model for targeted studies focused on rejuvenating HIV-specific CD8+ T cell responses.

UR - http://www.scopus.com/inward/record.url?scp=84912572257&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84912572257&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1400961

DO - 10.4049/jimmunol.1400961

M3 - Article

VL - 193

SP - 5576

EP - 5583

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 11

ER -