Activation of miR-21-Regulated Pathways in Immune Aging Selects against Signatures Characteristic of Memory T Cells

Chulwoo Kim; Bin Hu; Rohit R. Jadhav; Jun Jin; Huimin Zhang; Mary M. Cavanagh; Rama S. Akondy; Rafi Ahmed; Cornelia M. Weyand; Jörg J. Goronzy

doi:10.1016/j.celrep.2018.10.074

Activation of miR-21-Regulated Pathways in Immune Aging Selects against Signatures Characteristic of Memory T Cells

Chulwoo Kim, Bin Hu, Rohit R. Jadhav, Jun Jin, Huimin Zhang, Mary M. Cavanagh, Rama S. Akondy, Rafi Ahmed, Cornelia M. Weyand, Jörg J. Goronzy

Research output: Contribution to journal › Article › peer-review

73 Citations (Scopus)

Abstract

Induction of protective vaccine responses, governed by the successful generation of antigen-specific antibodies and long-lived memory T cells, is increasingly impaired with age. Regulation of the T cell proteome by a dynamic network of microRNAs is crucial to T cell responses. Here, we show that activation-induced upregulation of miR-21 biases the transcriptome of differentiating T cells away from memory T cells and toward inflammatory effector T cells. Such a transcriptome bias is also characteristic of T cell responses in older individuals who have increased miR-21 expression and is reversed by antagonizing miR-21. miR-21 targets negative feedback circuits in several signaling pathways. The concerted, sustained activity of these signaling pathways in miR-21^high T cells disfavors the induction of transcription factor networks involved in memory cell differentiation. Our data suggest that curbing miR-21 upregulation or activity in older individuals may improve their ability to mount effective vaccine responses. A hallmark of the aging immune system is its failure to induce long-lived memory. Kim et al. report that increased expression of miR-21 in naive T cells from older individuals sustains signaling in the MAPK and AKT-mTORC pathways, disfavoring induction of transcription factor networks involved in memory cell generation.

Original language	English
Pages (from-to)	2148-2162.e5
Journal	Cell Reports
Volume	25
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2018.10.074
Publication status	Published - 2018 Nov 20
Externally published	Yes

Bibliographical note

Funding Information:
We thank Corey Cain, Lusijah Sutherland, and the Palo Alto VA Flow Cytometry Core for assistance with flow cytometry and cell sorting. This work was supported by the NIH ( R01 AR042527 , R01 HL117913 , R01 AI108906 , and P01 HL129941 to C.M.W. and R01 AI108891 , R01 AG045779 , U19 AI057266 , R01 AI129191 , and I01 BX001669 to J.J.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Publisher Copyright:
© 2018 The Authors

Keywords

T cell differentiation
T memory cell
immune aging
immunosenescence
microRNA
short-lived T effector cell
vaccination

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2018.10.074

Cite this

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title = "Activation of miR-21-Regulated Pathways in Immune Aging Selects against Signatures Characteristic of Memory T Cells",

abstract = "Induction of protective vaccine responses, governed by the successful generation of antigen-specific antibodies and long-lived memory T cells, is increasingly impaired with age. Regulation of the T cell proteome by a dynamic network of microRNAs is crucial to T cell responses. Here, we show that activation-induced upregulation of miR-21 biases the transcriptome of differentiating T cells away from memory T cells and toward inflammatory effector T cells. Such a transcriptome bias is also characteristic of T cell responses in older individuals who have increased miR-21 expression and is reversed by antagonizing miR-21. miR-21 targets negative feedback circuits in several signaling pathways. The concerted, sustained activity of these signaling pathways in miR-21high T cells disfavors the induction of transcription factor networks involved in memory cell differentiation. Our data suggest that curbing miR-21 upregulation or activity in older individuals may improve their ability to mount effective vaccine responses. A hallmark of the aging immune system is its failure to induce long-lived memory. Kim et al. report that increased expression of miR-21 in naive T cells from older individuals sustains signaling in the MAPK and AKT-mTORC pathways, disfavoring induction of transcription factor networks involved in memory cell generation.",

keywords = "T cell differentiation, T memory cell, immune aging, immunosenescence, microRNA, short-lived T effector cell, vaccination",

author = "Chulwoo Kim and Bin Hu and Jadhav, {Rohit R.} and Jun Jin and Huimin Zhang and Cavanagh, {Mary M.} and Akondy, {Rama S.} and Rafi Ahmed and Weyand, {Cornelia M.} and Goronzy, {J{\"o}rg J.}",

note = "Funding Information: We thank Corey Cain, Lusijah Sutherland, and the Palo Alto VA Flow Cytometry Core for assistance with flow cytometry and cell sorting. This work was supported by the NIH ( R01 AR042527 , R01 HL117913 , R01 AI108906 , and P01 HL129941 to C.M.W. and R01 AI108891 , R01 AG045779 , U19 AI057266 , R01 AI129191 , and I01 BX001669 to J.J.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: {\textcopyright} 2018 The Authors",

year = "2018",

month = nov,

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doi = "10.1016/j.celrep.2018.10.074",

language = "English",

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AU - Kim, Chulwoo

AU - Hu, Bin

AU - Jadhav, Rohit R.

AU - Jin, Jun

AU - Zhang, Huimin

AU - Cavanagh, Mary M.

AU - Akondy, Rama S.

AU - Ahmed, Rafi

AU - Weyand, Cornelia M.

AU - Goronzy, Jörg J.

N1 - Funding Information: We thank Corey Cain, Lusijah Sutherland, and the Palo Alto VA Flow Cytometry Core for assistance with flow cytometry and cell sorting. This work was supported by the NIH ( R01 AR042527 , R01 HL117913 , R01 AI108906 , and P01 HL129941 to C.M.W. and R01 AI108891 , R01 AG045779 , U19 AI057266 , R01 AI129191 , and I01 BX001669 to J.J.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: © 2018 The Authors

PY - 2018/11/20

Y1 - 2018/11/20

N2 - Induction of protective vaccine responses, governed by the successful generation of antigen-specific antibodies and long-lived memory T cells, is increasingly impaired with age. Regulation of the T cell proteome by a dynamic network of microRNAs is crucial to T cell responses. Here, we show that activation-induced upregulation of miR-21 biases the transcriptome of differentiating T cells away from memory T cells and toward inflammatory effector T cells. Such a transcriptome bias is also characteristic of T cell responses in older individuals who have increased miR-21 expression and is reversed by antagonizing miR-21. miR-21 targets negative feedback circuits in several signaling pathways. The concerted, sustained activity of these signaling pathways in miR-21high T cells disfavors the induction of transcription factor networks involved in memory cell differentiation. Our data suggest that curbing miR-21 upregulation or activity in older individuals may improve their ability to mount effective vaccine responses. A hallmark of the aging immune system is its failure to induce long-lived memory. Kim et al. report that increased expression of miR-21 in naive T cells from older individuals sustains signaling in the MAPK and AKT-mTORC pathways, disfavoring induction of transcription factor networks involved in memory cell generation.

AB - Induction of protective vaccine responses, governed by the successful generation of antigen-specific antibodies and long-lived memory T cells, is increasingly impaired with age. Regulation of the T cell proteome by a dynamic network of microRNAs is crucial to T cell responses. Here, we show that activation-induced upregulation of miR-21 biases the transcriptome of differentiating T cells away from memory T cells and toward inflammatory effector T cells. Such a transcriptome bias is also characteristic of T cell responses in older individuals who have increased miR-21 expression and is reversed by antagonizing miR-21. miR-21 targets negative feedback circuits in several signaling pathways. The concerted, sustained activity of these signaling pathways in miR-21high T cells disfavors the induction of transcription factor networks involved in memory cell differentiation. Our data suggest that curbing miR-21 upregulation or activity in older individuals may improve their ability to mount effective vaccine responses. A hallmark of the aging immune system is its failure to induce long-lived memory. Kim et al. report that increased expression of miR-21 in naive T cells from older individuals sustains signaling in the MAPK and AKT-mTORC pathways, disfavoring induction of transcription factor networks involved in memory cell generation.

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KW - T memory cell

KW - immune aging

KW - immunosenescence

KW - microRNA

KW - short-lived T effector cell

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SN - 2211-1247

VL - 25

SP - 2148-2162.e5

JO - Cell Reports

JF - Cell Reports

IS - 8

ER -

Activation of miR-21-Regulated Pathways in Immune Aging Selects against Signatures Characteristic of Memory T Cells

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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