Trends in Immunology
ReviewImmune senescence special issue. Free access sponsored by the National Institutes of HealthCD28− T cells: their role in the age-associated decline of immune function
Introduction
The effectiveness of the immune response declines with age, particularly in the latter stages of life 1, 2, 3. Among the multiple complex factors that contribute to the age-associated changes of T cells in humans, the accumulation of CD28− T cells is one of the most profound and consistent 4, 5. At birth, virtually all human T cells express CD28; however, by age 80 and above, ∼10–15% of peripheral blood CD4 and 50–60% of CD8 T cells lack CD28 expression [6] (Figure 1). The increase of circulating CD28− T cells with age is observed in humans and non-human primates but not in mice [7]. Whether this discrepancy is related to differences in microbial exposure or something inherent to the aging of humans and primates remains to be elucidated.
CD28, an extensively studied co-stimulatory molecule, plays multiple roles during T-cell activation, proliferation and survival 8, 9. T cells that lose expression of CD28 display several striking features including reduced diversity of the T-cell receptor (TCR) [10] and defects in antigen-induced proliferation [11]. However, at the same time, CD28− T cells have enhanced cytotoxicity [11] and display suppressive functions [12]. Furthermore, the accumulation of CD28− T cells is associated with a reduced overall immune response to pathogens and vaccines in the elderly 13, 14.
CD28− T cells are heterogeneous populations and can be further divided into different subsets based on the expression of CD27, CD57 and other markers 15, 16, 17 (Figure 2). In CD8 T cells, the CD28−CD27− subset is considered to be close to terminal differentiation [18]. There is considerable interest in identifying the unique features of CD28− T cells as an important first step to understand age-associated changes in T cells and to subsequently develop potential intervention strategies to improve immune functions in the elderly.
Section snippets
Origin of CD28− T cells
Virtually all naïve T cells in umbilical cord blood express CD28 [19]; however, a dominant fraction of peripheral blood T cells become CD28− during aging [6]. The cause of loss of CD28 expression in T cells with age has been attributed to repeated antigenic stimulation, which can also be observed in CD28+ T cells after repeated antigen stimulation in vitro 20, 21. This activation-induced progressive loss of CD28 culminates in a T-cell population that is entirely CD28− in vitro 21, 22. The
Regulation of CD28 expression in aged cells
CD28 downregulation with T-cell activation involves transcriptional repression and increased protein turnover and has been interpreted as a negative feedback mechanism 33, 34. During normal antigenic exposure, CD28 expression is reduced but rapidly returns to the same level as that before stimulation. However, with sustained T-cell stimulation and turnover, CD28 expression decreases and is eventually lost. CD28 can be initially reinduced by IL-12 [35], but once firmly established, CD28 loss is
Molecular features of CD28− T cells
The completion of the human genome sequence and advances in gene expression analysis allow one to directly examine the genome-wide gene expression features of CD28− T cells 49, 50, 51, 52. These analyses have revealed a small set of genes that significantly alter their expression levels between CD28− and their CD28+ T-cell counterparts. These differentially expressed genes are shared to a great degree between CD4 and CD8 T cells and seem to be associated with the differentiation states of these
Functional characteristics of CD28− T cells
Early studies showed that the loss of CD28 was associated with a change of cellular function in T cells including a decreased response to anti-CD3 stimulation, decreased ability to secrete IL-2 after activation [62], decreased ability to upregulate telomerase after activation 21, 63 and increased susceptibility to activation-induced cell death [28]. In addition, the shorter telomeres in CD28− compared with CD28+ T cells 23, 64 might be because CD28 signaling is required for optimal telomerase
CD28− T cells in disease
Increased frequencies of CD28− T cells are common features of immune aging and chronic viral infections (Box 1). The expansion of CD28− CD4 T cells with age is usually relatively small, whereas CD28− CD8 T cells predominate (Figure 1). In the otherwise healthy elderly, CD28− CD8 T cells are frequently specific for CMV and Epstein-Barr virus (EBV) antigens. As discussed above, these cells have a negative impact on the adaptive immune system through a variety of mechanisms. One suggestion is that
Conclusion
Substantial progress has been made in understanding the molecular, cellular and functional features of CD28− T cells since their initial identification in the early 1990 s. From the characterization of the loss of function (oligoclonality, antigen-mediated proliferation deficiency and reduced replicative lifespan) to the gain of function (enhanced cytotoxicity and immunoregulation), the multifaceted nature of CD28− T cells has become increasingly clear. The current challenges are to elucidate
Acknowledgements
N-P.W. was supported by the Intramural Research Programs of the National Institute on Aging, National Institutes of Health (NIH). A.N.A. is supported by the British Biotechnological and Biological Sciences Research Council. J.G. is supported by RO1-AR41974, RO1-AG15043 and U19-AI57266.
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