Aging promotes acquisition of naive-like CD8+ memory T cell traits and enhanced functionalities
Jens Eberlein, Bennett Davenport, Tom Nguyen, Francisco Victorino, Kelsey Haist, Kevin Jhun, Anis Karimpour-Fard, Lawrence Hunter, Ross Kedl, Eric T. Clambey, Dirk Homann
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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Research Article Immunology

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

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 9

Delaying the maturation process of CD8+ TM: virus-titration chimeras.

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Delaying the maturation process of CD8+ TM: virus-titration chimeras. (A...
(A) Virus-titration chimeras were constructed with 104 p14+ TN, challenged with graded dosages of LCMV Armstrong (2 × 103 to 2 × 107 PFU), and early p14+ TE expansions were quantified in blood (days 5–7); note the 64-fold difference (P = 0.006) between low-dose (LCMV2e3) and high-dose (LCMV2e7) virus-titration chimeras on day 5. (B) Kinetics of p14+ TE and TM development in peripheral blood of virus-titration chimeras; vertical colored lines indicate time of respective peak expansions. (C) p14+ TM numbers in blood (day 37) and spleen (day 42). (D) Relative kinetics of phenotypic p14+ TM differentiation as a function of virus challenge dosage were determined on days 42–49; data are displayed as in Figure 8F, and statistics compare p14+ TM properties of high-dose (2 × 107 PFU) vs. lower dose (≤2 × 106 PFU) virus-titration chimeras. (E) Pie chart summary of preceding analyses comprising 50 markers stratified according to similarity between young p14+ TM recovered from LCMV2e3 virus-titration chimeras (6–7 weeks old) and old DbNP396+CD8+ TM (≥80 weeks old). (F) Functional properties of p14+ TM (day 42) were determined after a 5-hour peptide stimulation (IFN-γ, IL-2, CD40L, FasL, XCL1, CD107a), or directly ex vivo (GZMA). (G) AT/rechallenge experiments were performed with 2 × 103 p14+ TM purified from virus-titration chimeras (day 42) and II° p14+ TE expansion analyses on day 8. All summary data obtained with n ≥ 3 mice/group in multiple independent experiments. *P < 0.05, **P < 0.01, and ***P < 0.001 by 1-way ANOVA. PBMC, peripheral blood mononuclear cells.