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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 1

Enhanced II° reactivity of aged CD8+ TM.

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Enhanced II° reactivity of aged CD8+ TM.
(A) Outline for mixed AT/rechal...
(A) Outline for mixed AT/rechallenge experiments. Unless noted otherwise, CD8+ T cell–enriched populations containing 2 × 103 congenic young (Y) and old (O) DbNP396+CD8+ TM each were transferred i.v. into congenic recipients prior to i.p. LCMV challenge and analysis of II° CD8+ TE expansions on day 8. (B) Relative frequencies of II° DbNP396+CD8+ TE among all donor CD8+ T cells; donor age (time after I° LCMV challenge), factor of differential II° expansion and statistical significance are indicated. (C) Respective frequencies of NP396-specific II° CD8+ TE in young and old CD8+ donor T cell compartments as assessed by tetramer or IFN-γ staining. (D) Mixed AT/rechallenge experiments were conducted with CFSE-labeled donor cells to calculate proliferation indices; corresponding data points from individual recipients are connected by a line. (E) Expansion kinetics of II° CD8+ TE in peripheral blood (dot plots gated on all donor CD8+ T cells). (F–H) AT/rechallenge experiments were performed with CFSE-labeled p14+ TM. (I) II° DbNP396+CD8+ TE responses analyzed on day 5. To visualize earlier stages of the II° response in panels D–I, escalating numbers of CD8+ T cell–enriched donor populations were transferred containing (a) 2 × 105, (b) 4 × 104 or (c) 5 × 103 young and old DbNP396+CD8+ TM each, or (d) 1 × 106 p14+ TM. Data are the mean ± 1 SEM or feature individual data points with n ≥ 3 mice for multiple independent experiments. *P < 0.05, **P < 0.01, and ***P < 0.001 by 1 way ANOVA or Student’s t test. BM, bone marrow; MedLN, mediastinal lymph nodes; MLN, mesenteric lymph nodes; PBMC, peripheral blood mononuclear cells; PC, peritoneal cavity.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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