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. 2011 Aug 16;108(33):13694-9.
doi: 10.1073/pnas.1107594108. Epub 2011 Aug 3.

Nonrandom attrition of the naive CD8+ T-cell pool with aging governed by T-cell receptor:pMHC interactions

Brian D Rudd  1 , Vanessa Venturi, Gang Li, Partha Samadder, James M Ertelt, Sing Sing Way, Miles P Davenport, Janko Nikolich-Žugich
Affiliations

Nonrandom attrition of the naive CD8+ T-cell pool with aging governed by T-cell receptor:pMHC interactions

Brian D Rudd et al. Proc Natl Acad Sci U S A. .

Abstract

Immunity against new infections declines in the last quartile of life, as do numbers of naive T cells. Peripheral maintenance of naive T cells over the lifespan is necessary because their production drastically declines by puberty, a result of thymic involution. We report that this maintenance is not random in advanced aging. As numbers and diversity of naive CD8(+) T cells declined with aging, surviving cells underwent faster rates of homeostatic proliferation, were selected for high T-cell receptor:pMHC avidity, and preferentially acquired "memory-like" phenotype. These high-avidity precursors preferentially responded to infection and exhibited strong antimicrobial function. Thus, T-cell receptor avidity for self-pMHC provides a proofreading mechanism to maintain some of the fittest T cells in the otherwise crumbling naive repertoire, providing a degree of compensation for numerical and diversity defects in old T cells.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
The size of the gB-8p precursor pool in unprimed mice declines with age and preferentially acquires a “memory-like” phenotype. (A) Total numbers of gB-8p–specific CD8+ T cells recovered from individual naive mice at 2 to 3, 18, and 22 mo of age. Phenotypic analysis of gB-8p precursors was also performed. The proportion of the naïve gB-8p pool that is CD62hi (B) or CD44hi (C) in different aged mice is shown. All data are pooled from three separate experiments. Results depict mean ± SEM, ***P < 0.001.
Fig. 2.
Fig. 2.
The aging gB-8p precursor pool in unprimed mice becomes biased toward CD44hi Vβ10+ cells. (A) The proportion of the naive gB-8p pool that uses Vβ10 in different aged mice was assessed by flow cytometry. (B) The frequencies of CD44hi memory phenotype cells within the Vβ10+ and Vβ10− gB-8p populations are also shown. All data are pooled from at least three separate experiments. Results depict mean ± SEM from n > 13 mice/group. *P < 0.05, ***P < 0.001.
Fig. 3.
Fig. 3.
Vb10+ gB-8p precursors undergo faster rates of homeostatic proliferation caused by stronger interactions with peptide:MHC complexes. (A) “Untouched” old adult CD8+ T cells (2–3 mo old) were transferred into Rag1−/− mice and the percentage of Vb10+ gB-8p cells were determined 1 mo later. (B) Adult mice (2–3 mo old) were given BrdU in their drinking and the amounts of BrdU incorporated (mean fluouresence intensity, MFI) within Vβ10+ and Vβ10− gB-8p precursors was measured 1 mo later. (C) Expression levels of CD5 (MFI) within Vβ10+ and Vβ10− gB-8p precursors isolated from adult mice (2-3 mo old). (D) The tetramer dissociation assay was performed on naive adult gB-8p precursors (2–3 mo old). The percentage of Vβ10+ cells within the high-avidity fraction (or those that were still tetramer-bound at the end of the assay) was compared with the levels observed in the total gB-8p population. All data are pooled from at least two separate experiments, with n ≥ 3 mice per group per experiment. Results depict mean ± SEM, ***P < 0.001.
Fig. 4.
Fig. 4.
Clonotypic composition of Vb10+ gB-8p precursors from unprimed mice at different ages. The percentages of unique TCRβ clonotypes pooled across all mice (n = 6–8) per age group that have a particular (A) CDR3β length and (B) Jβ gene use. The diversities of the TCRβ repertoires for individual mice were evaluated using (C) the number of different TCRβ clonotypes. A Mann–Whitney test was used for each pairwise comparison between age groups, with the statistical significance for each pairwise comparison determined at *P < 0.0167, using Bonferroni correction for multiple pairwise comparisons.
Fig. 5.
Fig. 5.
The reduced gB-8p response to LM-gB in old mice is dominated by high-avidity Vb10+ gB-8p cells. Different aged mice were infected with 5,000 CFU LM-gB. At 7 d postinfection, the total number (A) and Vb10 use (B) of gB-8p cells in the spleen were evaluated. TCR:pMHC off-rates (tetramer decay) determination in Vβ10+ and Vβ10− gB-8p cells (C and D) was also assessed at 7 d after LM-gB infection. All data are representative of at least two separate experiments with n ≥ 7 mice per group. Results depict mean ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001.
Fig. 6.
Fig. 6.
Immune responsiveness is preferentially maintained within old Vb10+ gB-8p precursors. (A) Different aged mice were infected with 5,000 CFU LM-gB and given BrdU in their drinking water. At 3 d postinfection, gB-8p cells were isolated and the percentage of BrdU+ cells within the Vβ10+ and Vβ10− fractions were evaluated. (B) LM-gB infected mice were pulsed with 0.8 mg BrdU (i.p.) on day 6 and the percentage of BrdU+ cells was analyzed in splenic Vβ10+ and Vβ10− gB-8p cells on day 7 postinfection. (C) Polyfunctional CD8+ T cells or those that are capable of simultaneously producing IFN-γ, TNF-α, and Granzyme B following gB-8p peptide stimulation were calculated at 7 d postinfection. (D) The MFI of Granzyme B produced individually by Vβ10+ and Vβ10− gB-8p-specific CD8+ T cells is also shown. Data shown in A were pooled from two separate experiments, with n = 3 mice per group per experiment. Data shown in B to D are representative of at least two separate experiments with n = 5–8 mice per group. Results depict mean ± SEM, *P < 0.05, **P < 0.01, ***P < 0.001.
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