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Aging promotes acquisition of naive-like CD8+ memory T cell traits and enhanced functionalities
Jens Eberlein, … , Eric T. Clambey, Dirk Homann
Jens Eberlein, … , Eric T. Clambey, Dirk Homann
Published September 12, 2016
Citation Information: J Clin Invest. 2016;126(10):3942-3960. https://doi.org/10.1172/JCI88546.
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Research Article Immunology

Aging promotes acquisition of naive-like CD8+ memory T cell traits and enhanced functionalities

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Abstract

Protective T cell memory is an acquired trait that is contingent upon the preservation of its constituents and therefore vulnerable to the potentially deleterious effects of organismal aging. Here, however, we have found that long-term T cell memory in a natural murine host-pathogen system can substantially improve over time. Comprehensive molecular, phenotypic, and functional profiling of aging antiviral CD8+ memory T cells (CD8+ TM) revealed a pervasive remodeling process that promotes the gradual acquisition of distinct molecular signatures, of increasingly homogeneous phenotypes, and of diversified functionalities that combine to confer a CD8+ TM–autonomous capacity for enhanced recall responses and immune protection. Notably, the process of CD8+ TM aging is characterized by a progressive harmonization of memory and naive T cell traits, is broadly amenable to experimental acceleration or retardation, and serves as a constitutional component for the “rebound model” of memory T cell maturation. By casting CD8+ TM populations within the temporal framework of their slowly evolving properties, this model establishes a simple ontogenetic perspective on the principal organization of CD8+ T cell memory that may directly inform the development of improved diagnostic, prophylactic, and therapeutic modalities.

Authors

Jens Eberlein, Bennett Davenport, Tom Nguyen, Francisco Victorino, Kelsey Haist, Kevin Jhun, Anis Karimpour-Fard, Lawrence Hunter, Ross Kedl, Eric T. Clambey, Dirk Homann

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Figure 7

Evolving functionalities of aging antiviral CD8+ TM: granzymes, degranulation, and CTL activity.

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Evolving functionalities of aging antiviral CD8+ TM: granzymes, degranul...
(A) Temporal regulation of granzyme mRNA (p14+ TE/M, microarray data) and protein (DbNP396+CD8+ TE/M) expression analyzed directly ex vivo. (B) Lamp1, -2, and -3 mRNA expression and degranulation capacity of aging p14+ TE/M and NP396-specific CD8+ TM, respectively. (C) Left, young (Y) and old (O) LCMV-immune mice harboring identical numbers of blood-borne CD8+ TM were used to assess CD8+ TM CTL activities in vivo; middle, killing kinetics determined in blood after AT of 4.5 × 106 differentially CFSE-labeled control and NP396 peptide–coated target cells each (histograms gated on target cells retrieved 5 hours after AT into LCMV-immune [young, gray; old, black] or naive [open] mice); right, splenic DbNP396+CD8+ TM numbers at conclusion of assay and extent of specific killing. (D) DbNP396+CD8+ TM abundance and killing activity in spleen after AT of 4.5 × 105 purified young or old DbNP396+CD8+ TM into naive recipients followed by transfer of 4.5 × 105 sensitized and control target cells each; data generated with n ≥ 3 mice/group in multiple independent experiments. *P < 0.05, **P < 0.01, and ***P < 0.001 by 1-way ANOVA or Student’s t test. PBMC, peripheral blood mononuclear cells.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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