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Contributed by Peter C. Doherty, December 22, 2015 (sent for review November 30, 2015; reviewed by Marcia A. Blackman and Stanley Perlman)
Significance
Compromised CD8+ T-cell immunity is associated with significant morbidity and mortality in the elderly. Whereas the number of naïve CD8+ T cells declines with age, the drivers of loss and consequences for clonal composition are unclear. We show that aging disproportionately impacts small naïve CD8+ T-cell populations. For one CD8+ T-cell population, loss of diversity was minimally attributable to expansion but rather was associated with diminished cell number and selective retention of cells exhibiting markers of heightened self, but not foreign, recognition. Thus, vaccine formulations for the elderly may benefit from targeting naïve antigen-specific populations with relatively high precursor frequency and self-reactivity, and retention of high-quality T cells may be achieved through repeated low-level T-cell receptor stimulation.
Abstract
In advanced age, decreased CD8+ cytotoxic T-lymphocyte (CTL) responses to novel pathogens and cancer is paralleled by a decline in the number and function of naïve CTL precursors (CTLp). Although the age-related fall in CD8+ T-cell numbers is well established, neither the underlying mechanisms nor the extent of variation for different epitope specificities have been defined. Furthermore, naïve CD8+ T cells expressing high levels of CD44 accumulate with age, but it is unknown whether this accumulation reflects their preferential survival or an age-dependent driver of CD8+ T-cell proliferation. Here, we track the number and phenotype of four influenza A virus (IAV)-specific CTLp populations in naïve C57BL/6 (B6) mice during aging, and compare T-cell receptor (TCR) clonal diversity for the CD44hi and CD44lo subsets of one such population. We show differential onset of decline for several IAV-specific CD8+ T-cell populations with advanced age that parallel age-associated changes in the B6 immunodominance hierarchy, suggestive of distinct impacts of aging on different epitope-specific populations. Despite finding no evidence of clonal expansions in an aged, epitope-specific TCR repertoire, nonrandom alterations in TCR usage were observed, along with elevated CD5 and CD8 coreceptor expression. Collectively, these data demonstrate that naïve CD8+ T cells expressing markers of heightened self-recognition are selectively retained, but not clonally expanded, during aging.
Footnotes
- ↵1To whom correspondence may be addressed. Email: pcd{at}unimelb.edu.au or nllg{at}unimelb.edu.au.
Author contributions: K.M.Q., P.C.D., A.H., and N.L.L.G. designed research; K.M.Q., T.C., W.-T.K., X.Y.X.S., M.M., K.A.W., and N.L.L.G. performed research; S.G.Z., J.M.M., P.G.T., and A.H. contributed new reagents/analytic tools; K.M.Q., S.G.Z., T.C., W.-T.K., X.Y.X.S., M.M., K.A.W., J.M.M., P.G.T., A.H., and N.L.L.G. analyzed data; and K.M.Q., P.C.D., and N.L.L.G. wrote the paper.
Reviewers: M.A.B., Trudeau Institute; and S.P., University of Iowa.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1525167113/-/DCSupplemental.
http://www.pnas.org/preview_site/misc/userlicense.xhtml
Naïve CD8+ T cells in aging
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