Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK+ CD8+ T Cells as Conserved Hallmark of Inflammaging

Denis A. Mogilenko; Oleg Shpynov; Prabhakar Sairam Andhey; Laura Arthur; Amanda Swain; Ekaterina Esaulova; Simone Brioschi; Irina Shchukina; Martina Kerndl; Monika Bambouskova; Zhangting Yao; Anwesha Laha; Konstantin Zaitsev; Samantha Burdess; Susan Gillfilan; Sheila A. Stewart; Marco Colonna; Maxim N. Artyomov

doi:10.1016/j.immuni.2020.11.005

Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK⁺ CD8⁺ T Cells as Conserved Hallmark of Inflammaging

Denis A. Mogilenko, Oleg Shpynov, Prabhakar Sairam Andhey, Laura Arthur, Amanda Swain, Ekaterina Esaulova, Simone Brioschi, Irina Shchukina, Martina Kerndl, Monika Bambouskova, Zhangting Yao, Anwesha Laha, Konstantin Zaitsev, Samantha Burdess, Susan Gillfilan, Sheila A. Stewart, Marco Colonna, Maxim N. Artyomov

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Abstract

Systematic understanding of immune aging on a whole-body scale is currently lacking. We characterized age-associated alterations in immune cells across multiple mouse organs using single-cell RNA and antigen receptor sequencing and flow cytometry-based validation. We defined organ-specific and common immune alterations and identified a subpopulation of age-associated granzyme K (GZMK)-expressing CD8⁺ T (Taa) cells that are distinct from T effector memory (Tem) cells. Taa cells were highly clonal, had specific epigenetic and transcriptional signatures, developed in response to an aged host environment, and expressed markers of exhaustion and tissue homing. Activated Taa cells were the primary source of GZMK, which enhanced inflammatory functions of non-immune cells. In humans, proportions of the circulating GZMK⁺CD8⁺ T cell population that shares transcriptional and epigenetic signatures with mouse Taa cells increased during healthy aging. These results identify GZMK⁺ Taa cells as a potential target to address age-associated dysfunctions of the immune system.

Original language	English
Pages (from-to)	99-115.e12
Journal	Immunity
Volume	54
Issue number	1
DOIs	https://doi.org/10.1016/j.immuni.2020.11.005
State	Published - Jan 12 2021

Keywords

Aging
CD8 T cells
CITE-seq
granzyme K
immune system
inflammaging
single-cell ATAC-sequencing
single-cell BCR-sequencing
single-cell RNA-sequencing
single-cell TCR-sequencing

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10.1016/j.immuni.2020.11.005

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Mogilenko, D. A., Shpynov, O., Andhey, P. S., Arthur, L., Swain, A., Esaulova, E., Brioschi, S., Shchukina, I., Kerndl, M., Bambouskova, M., Yao, Z., Laha, A., Zaitsev, K., Burdess, S., Gillfilan, S., Stewart, S. A., Colonna, M., & Artyomov, M. N. (2021). Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK⁺ CD8⁺ T Cells as Conserved Hallmark of Inflammaging. Immunity, 54(1), 99-115.e12. https://doi.org/10.1016/j.immuni.2020.11.005

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title = "Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK+ CD8+ T Cells as Conserved Hallmark of Inflammaging",

abstract = "Systematic understanding of immune aging on a whole-body scale is currently lacking. We characterized age-associated alterations in immune cells across multiple mouse organs using single-cell RNA and antigen receptor sequencing and flow cytometry-based validation. We defined organ-specific and common immune alterations and identified a subpopulation of age-associated granzyme K (GZMK)-expressing CD8+ T (Taa) cells that are distinct from T effector memory (Tem) cells. Taa cells were highly clonal, had specific epigenetic and transcriptional signatures, developed in response to an aged host environment, and expressed markers of exhaustion and tissue homing. Activated Taa cells were the primary source of GZMK, which enhanced inflammatory functions of non-immune cells. In humans, proportions of the circulating GZMK+CD8+ T cell population that shares transcriptional and epigenetic signatures with mouse Taa cells increased during healthy aging. These results identify GZMK+ Taa cells as a potential target to address age-associated dysfunctions of the immune system.",

keywords = "Aging, CD8 T cells, CITE-seq, granzyme K, immune system, inflammaging, single-cell ATAC-sequencing, single-cell BCR-sequencing, single-cell RNA-sequencing, single-cell TCR-sequencing",

author = "Mogilenko, {Denis A.} and Oleg Shpynov and Andhey, {Prabhakar Sairam} and Laura Arthur and Amanda Swain and Ekaterina Esaulova and Simone Brioschi and Irina Shchukina and Martina Kerndl and Monika Bambouskova and Zhangting Yao and Anwesha Laha and Konstantin Zaitsev and Samantha Burdess and Susan Gillfilan and Stewart, {Sheila A.} and Marco Colonna and Artyomov, {Maxim N.}",

note = "Funding Information: The work was supported by grant from Aging Biology Foundation (USA) (M.N.A.) and NIH grants CA217208-01A1 and AG059244-01A1 (S.A.S.). We would like to thank Dr. Gwendalyn Randolph and Peter Wang for providing Cx3cr1-GFP reporter mice, Dr. Diane Bender for assistance with multiplex techniques, and Dorjan Brinja and Dr. Erica Lantelme for assistance with cell sorting. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2021",

month = jan,

day = "12",

doi = "10.1016/j.immuni.2020.11.005",

language = "English",

volume = "54",

pages = "99--115.e12",

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Mogilenko, DA, Shpynov, O, Andhey, PS, Arthur, L, Swain, A, Esaulova, E, Brioschi, S, Shchukina, I, Kerndl, M, Bambouskova, M, Yao, Z, Laha, A, Zaitsev, K, Burdess, S, Gillfilan, S, Stewart, SA , Colonna, M & Artyomov, MN 2021, 'Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK⁺ CD8⁺ T Cells as Conserved Hallmark of Inflammaging', Immunity, vol. 54, no. 1, pp. 99-115.e12. https://doi.org/10.1016/j.immuni.2020.11.005

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T1 - Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK+ CD8+ T Cells as Conserved Hallmark of Inflammaging

AU - Mogilenko, Denis A.

AU - Shpynov, Oleg

AU - Andhey, Prabhakar Sairam

AU - Arthur, Laura

AU - Swain, Amanda

AU - Esaulova, Ekaterina

AU - Brioschi, Simone

AU - Shchukina, Irina

AU - Kerndl, Martina

AU - Bambouskova, Monika

AU - Yao, Zhangting

AU - Laha, Anwesha

AU - Zaitsev, Konstantin

AU - Burdess, Samantha

AU - Gillfilan, Susan

AU - Stewart, Sheila A.

AU - Colonna, Marco

AU - Artyomov, Maxim N.

N1 - Funding Information: The work was supported by grant from Aging Biology Foundation (USA) (M.N.A.) and NIH grants CA217208-01A1 and AG059244-01A1 (S.A.S.). We would like to thank Dr. Gwendalyn Randolph and Peter Wang for providing Cx3cr1-GFP reporter mice, Dr. Diane Bender for assistance with multiplex techniques, and Dorjan Brinja and Dr. Erica Lantelme for assistance with cell sorting. Publisher Copyright: © 2020 Elsevier Inc.

PY - 2021/1/12

Y1 - 2021/1/12

N2 - Systematic understanding of immune aging on a whole-body scale is currently lacking. We characterized age-associated alterations in immune cells across multiple mouse organs using single-cell RNA and antigen receptor sequencing and flow cytometry-based validation. We defined organ-specific and common immune alterations and identified a subpopulation of age-associated granzyme K (GZMK)-expressing CD8+ T (Taa) cells that are distinct from T effector memory (Tem) cells. Taa cells were highly clonal, had specific epigenetic and transcriptional signatures, developed in response to an aged host environment, and expressed markers of exhaustion and tissue homing. Activated Taa cells were the primary source of GZMK, which enhanced inflammatory functions of non-immune cells. In humans, proportions of the circulating GZMK+CD8+ T cell population that shares transcriptional and epigenetic signatures with mouse Taa cells increased during healthy aging. These results identify GZMK+ Taa cells as a potential target to address age-associated dysfunctions of the immune system.

AB - Systematic understanding of immune aging on a whole-body scale is currently lacking. We characterized age-associated alterations in immune cells across multiple mouse organs using single-cell RNA and antigen receptor sequencing and flow cytometry-based validation. We defined organ-specific and common immune alterations and identified a subpopulation of age-associated granzyme K (GZMK)-expressing CD8+ T (Taa) cells that are distinct from T effector memory (Tem) cells. Taa cells were highly clonal, had specific epigenetic and transcriptional signatures, developed in response to an aged host environment, and expressed markers of exhaustion and tissue homing. Activated Taa cells were the primary source of GZMK, which enhanced inflammatory functions of non-immune cells. In humans, proportions of the circulating GZMK+CD8+ T cell population that shares transcriptional and epigenetic signatures with mouse Taa cells increased during healthy aging. These results identify GZMK+ Taa cells as a potential target to address age-associated dysfunctions of the immune system.

KW - Aging

KW - CD8 T cells

KW - CITE-seq

KW - granzyme K

KW - immune system

KW - inflammaging

KW - single-cell ATAC-sequencing

KW - single-cell BCR-sequencing

KW - single-cell RNA-sequencing

KW - single-cell TCR-sequencing

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DO - 10.1016/j.immuni.2020.11.005

M3 - Article

C2 - 33271118

AN - SCOPUS:85097512844

VL - 54

SP - 99-115.e12

JO - Immunity

JF - Immunity

SN - 1074-7613

IS - 1

ER -

Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK⁺ CD8⁺ T Cells as Conserved Hallmark of Inflammaging

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Keywords

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