Age-Related Decline in Primary CD8+ T Cell Responses Is Associated with the Development of Senescence in Virtual Memory CD8+ T Cells

Kylie M. Quinn, Annette Fox, Kim L. Harland, Brendan E. Russ, Jasmine Li, Thi H.O. Nguyen, Liyen Loh, Moshe Olshanksy, Haroon Naeem, Kirill Tsyganov, Florian Wiede, Rosela Webster, Chantelle Blyth, Xavier Y.X. Sng, Tony Tiganis, David Powell, Peter C. Doherty, Stephen J. Turner, Katherine Kedzierska, Nicole L. La Gruta

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Abstract

Age-associated decreases in primary CD8+ T cell responses occur, in part, due to direct effects on naive CD8+ T cells to reduce intrinsic functionality, but the precise nature of this defect remains undefined. Aging also causes accumulation of antigen-naive but semi-differentiated “virtual memory” (TVM) cells, but their contribution to age-related functional decline is unclear. Here, we show that TVM cells are poorly proliferative in aged mice and humans, despite being highly proliferative in young individuals, while conventional naive T cells (TN cells) retain proliferative capacity in both aged mice and humans. Adoptive transfer experiments in mice illustrated that naive CD8 T cells can acquire a proliferative defect imposed by the aged environment but age-related proliferative dysfunction could not be rescued by a young environment. Molecular analyses demonstrate that aged TVM cells exhibit a profile consistent with senescence, marking an observation of senescence in an antigenically naive T cell population. CD8 T cell responses decline with age, but virtual memory T (TVM) cells accumulate. Quinn et al. demonstrate that TVM cells lose the ability to proliferate in response to TCR signals, but not IL-15, with increasing age. Aged TVM cells express transcriptional and phenotypic markers of senescence, rather than exhaustion.

Original languageEnglish
Pages (from-to)3512-3524
Number of pages13
JournalCell Reports
Volume23
Issue number12
DOIs
Publication statusPublished - 19 Jun 2018

Keywords

  • aging
  • CD8 T cells
  • cellular senescence
  • exhaustion
  • naive CD8 T cells
  • T cell dysfunction
  • virtual memory T cells

Cite this

Quinn, Kylie M. ; Fox, Annette ; Harland, Kim L. ; Russ, Brendan E. ; Li, Jasmine ; Nguyen, Thi H.O. ; Loh, Liyen ; Olshanksy, Moshe ; Naeem, Haroon ; Tsyganov, Kirill ; Wiede, Florian ; Webster, Rosela ; Blyth, Chantelle ; Sng, Xavier Y.X. ; Tiganis, Tony ; Powell, David ; Doherty, Peter C. ; Turner, Stephen J. ; Kedzierska, Katherine ; La Gruta, Nicole L. / Age-Related Decline in Primary CD8+ T Cell Responses Is Associated with the Development of Senescence in Virtual Memory CD8+ T Cells. In: Cell Reports. 2018 ; Vol. 23, No. 12. pp. 3512-3524.
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abstract = "Age-associated decreases in primary CD8+ T cell responses occur, in part, due to direct effects on naive CD8+ T cells to reduce intrinsic functionality, but the precise nature of this defect remains undefined. Aging also causes accumulation of antigen-naive but semi-differentiated “virtual memory” (TVM) cells, but their contribution to age-related functional decline is unclear. Here, we show that TVM cells are poorly proliferative in aged mice and humans, despite being highly proliferative in young individuals, while conventional naive T cells (TN cells) retain proliferative capacity in both aged mice and humans. Adoptive transfer experiments in mice illustrated that naive CD8 T cells can acquire a proliferative defect imposed by the aged environment but age-related proliferative dysfunction could not be rescued by a young environment. Molecular analyses demonstrate that aged TVM cells exhibit a profile consistent with senescence, marking an observation of senescence in an antigenically naive T cell population. CD8 T cell responses decline with age, but virtual memory T (TVM) cells accumulate. Quinn et al. demonstrate that TVM cells lose the ability to proliferate in response to TCR signals, but not IL-15, with increasing age. Aged TVM cells express transcriptional and phenotypic markers of senescence, rather than exhaustion.",
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author = "Quinn, {Kylie M.} and Annette Fox and Harland, {Kim L.} and Russ, {Brendan E.} and Jasmine Li and Nguyen, {Thi H.O.} and Liyen Loh and Moshe Olshanksy and Haroon Naeem and Kirill Tsyganov and Florian Wiede and Rosela Webster and Chantelle Blyth and Sng, {Xavier Y.X.} and Tony Tiganis and David Powell and Doherty, {Peter C.} and Turner, {Stephen J.} and Katherine Kedzierska and {La Gruta}, {Nicole L.}",
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Quinn, KM, Fox, A, Harland, KL, Russ, BE, Li, J, Nguyen, THO, Loh, L, Olshanksy, M, Naeem, H, Tsyganov, K, Wiede, F, Webster, R, Blyth, C, Sng, XYX, Tiganis, T, Powell, D, Doherty, PC, Turner, SJ, Kedzierska, K & La Gruta, NL 2018, 'Age-Related Decline in Primary CD8+ T Cell Responses Is Associated with the Development of Senescence in Virtual Memory CD8+ T Cells', Cell Reports, vol. 23, no. 12, pp. 3512-3524. https://doi.org/10.1016/j.celrep.2018.05.057

Age-Related Decline in Primary CD8+ T Cell Responses Is Associated with the Development of Senescence in Virtual Memory CD8+ T Cells. / Quinn, Kylie M.; Fox, Annette; Harland, Kim L.; Russ, Brendan E.; Li, Jasmine; Nguyen, Thi H.O.; Loh, Liyen; Olshanksy, Moshe; Naeem, Haroon; Tsyganov, Kirill; Wiede, Florian; Webster, Rosela; Blyth, Chantelle; Sng, Xavier Y.X.; Tiganis, Tony; Powell, David; Doherty, Peter C.; Turner, Stephen J.; Kedzierska, Katherine; La Gruta, Nicole L.

In: Cell Reports, Vol. 23, No. 12, 19.06.2018, p. 3512-3524.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Quinn, Kylie M.

AU - Fox, Annette

AU - Harland, Kim L.

AU - Russ, Brendan E.

AU - Li, Jasmine

AU - Nguyen, Thi H.O.

AU - Loh, Liyen

AU - Olshanksy, Moshe

AU - Naeem, Haroon

AU - Tsyganov, Kirill

AU - Wiede, Florian

AU - Webster, Rosela

AU - Blyth, Chantelle

AU - Sng, Xavier Y.X.

AU - Tiganis, Tony

AU - Powell, David

AU - Doherty, Peter C.

AU - Turner, Stephen J.

AU - Kedzierska, Katherine

AU - La Gruta, Nicole L.

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N2 - Age-associated decreases in primary CD8+ T cell responses occur, in part, due to direct effects on naive CD8+ T cells to reduce intrinsic functionality, but the precise nature of this defect remains undefined. Aging also causes accumulation of antigen-naive but semi-differentiated “virtual memory” (TVM) cells, but their contribution to age-related functional decline is unclear. Here, we show that TVM cells are poorly proliferative in aged mice and humans, despite being highly proliferative in young individuals, while conventional naive T cells (TN cells) retain proliferative capacity in both aged mice and humans. Adoptive transfer experiments in mice illustrated that naive CD8 T cells can acquire a proliferative defect imposed by the aged environment but age-related proliferative dysfunction could not be rescued by a young environment. Molecular analyses demonstrate that aged TVM cells exhibit a profile consistent with senescence, marking an observation of senescence in an antigenically naive T cell population. CD8 T cell responses decline with age, but virtual memory T (TVM) cells accumulate. Quinn et al. demonstrate that TVM cells lose the ability to proliferate in response to TCR signals, but not IL-15, with increasing age. Aged TVM cells express transcriptional and phenotypic markers of senescence, rather than exhaustion.

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