CD28− T cells: their role in the age-associated decline of immune function

doi:10.1016/j.it.2009.03.013

Trends in Immunology

Volume 30, Issue 7, July 2009, Pages 306-312

https://doi.org/10.1016/j.it.2009.03.013 Get rights and content

The accumulation of CD28⁻ T cells, particularly within the CD8 subset, is one of the most prominent changes during T-cell homeostasis and function associated with aging in humans. CD28, a major co-stimulatory receptor, is responsible for the optimal antigen-mediated T-cell activation, proliferation and survival of T cells. CD28⁻ T cells exhibit reduced antigen receptor diversity, defective antigen-induced proliferation and a shorter replicative lifespan while showing enhanced cytotoxicity and regulatory functions. Gene expression analyses reveal profound changes of CD28⁻ T cells in comparison to their CD28⁺ counterparts and corroborate their functional differences. Here we review recent advances in our understanding of CD28⁻ T cells and 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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Published by Elsevier Ltd.

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

Section snippets

Origin of CD28− T cells

Regulation of CD28 expression in aged cells

Molecular features of CD28− T cells

Functional characteristics of CD28− T cells

CD28− T cells in disease

Conclusion

Acknowledgements

Curr. Opin. Immunol.

Curr. Opin. Immunol.

Immunity

Trends Mol. Med.

Clin. Immunol.

Blood

Hum. Immunol.

Blood

Clin. Immunol.

Clin. Immunol. Immunopathol.

Mech. Ageing Dev.

Immunity

Blood

Semin. Immunol.

Mech. Ageing Dev.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Blood

Exp. Gerontol.

Clin. Immunol.

Cell

Hum. Immunol.

J. Biol. Chem.

J. Biol. Chem.

Cell

Am. J. Pathol.

The role of CD8+ T-cell replicative senescence in human aging

Immunol. Rev.

Expansion of cytotoxic CD8+CD28- T cells in healthy ageing people, including centenarians

Immunology

CD28/B7 system of T cell costimulation

Annu. Rev. Immunol.

CD28- T lymphocytes: antigenic and functional properties

J. Immunol.

Specific suppression of human CD4+ Th cell responses to pig MHC antigens by CD8+ CD28- Regulator T cells

J. Immunol.

Lack of antibody production following immunization in old age: association with CD8(+)CD28(−) T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines

J. Immunol.

Prognostic markers of radiographic progression in early rheumatoid arthritis

Arthritis Rheum.

The loss of telomerase activity in highly differentiated CD8+CD28-CD27- T cell is associated with decreased Akt (Ser473) phosphorylation

J. Immunol.

Phenotype and function of human T lymphocyte subsets: consensus and issues

Cytometry A

Human CD8(+) T-cell differentiation in response to viruses

Nat. Rev. Immunol.

CD28 co-stimulation of T-cell-mediated cytotoxicity

Int. J. Cancer Suppl.

CD28 extinction in human T cells: altered functions and the program of T-cell senescence

Immunol. Rev.

Modulation of CD28 expression: distinct regulatory pathways during activation and replicative senescence

J. Immunol.

Shortened telomeres in clonally expanded CD28-CD8+ T cells imply a replicative history that is distinct from their CD28+CD8+ counterparts

J. Immunol.

Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+CD28- cytotoxic effector clones

Int. Immunol.

Loss of CD28 expression on CD8(+) T cells is induced by IL-2 receptor gamma chain signalling cytokines and type I IFN, and increases susceptibility to activation-induced apoptosis

Int. Immunol.

Review
Immune senescence special issue. Free access sponsored by the National Institutes of Health
CD28⁻ T cells: their role in the age-associated decline of immune function

Origin of CD28⁻ T cells

Molecular features of CD28⁻ T cells

Functional characteristics of CD28⁻ T cells

CD28⁻ T cells in disease