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 4

Temporal regulation of C-type lectin expression by virus-specific CD8+ TE/M.

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Temporal regulation of C-type lectin expression by virus-specific CD8+ T...
The figure is organized into modules consisting of 3 panels each: left, mRNA expression (p14+ TE/M microarrays); middle, representative dot plots of young (top) and old (bottom) splenic CD8+ T cells unless indicated otherwise; right, temporal regulation of DbNP396+CD8+ TE/M properties. The gray bars demarcate the transition from TE to early TM stage (day 42), and the triangle symbols refer to CD44loCD8+ TN. All values are the mean ± 1 SEM with n ≥ 3 individual mice per time point; *P < 0.05, **P < 0.01, and ***P < 0.001 comparing young and older (> day 100) p14+ TM or DbNP396+CD8+ TM, respectively, using 1-way ANOVA. Significant differences emerging during the memory phase are highlighted in red (upregulation) or green (downregulation). This outline also serves as a template for Supplemental Figures 4–14 and the data are further summarized and expanded to related genes in Supplemental Table 4. (A) Temporal regulation of KLR expression. (B) Temporal regulation of CD62L and CD69 expression. (*) indicates statistical significance determined by Student’s t test rather than ANOVA. The insert in the CD69 module depicts young (gray, day 67) and old (black, day 725) DbNP396+CD8+ TM recovered from MLNs and a corresponding data summary (Y, day 66; O, day 563). MLN insert bar diagram analysis in (B) determined by Student’s t test.