T-cell senescence: a culprit of immune abnormalities in chronic inflammation and persistent infection

https://doi.org/10.1016/j.molmed.2004.01.002Get rights and content

Abstract

Long-lived clonal T cells deficient in CD28 expression are commonly found in patients with inflammatory syndromes and persistent infections. Considering that CD28 loss is the most consistent immunological marker of aging, we propose that, in pathological states, CD28null T cells represent prematurely senescent cells resulting from persistent immune activation. These unusual lymphocytes have aberrant functions that contribute to disease-related immune abnormalities, and the degree of accumulation of CD28null T cells predicts the severity of clinical manifestations. We suggest that understanding of the biological properties of T cells that have reached replicative senescence will influence the future management of certain diseases. Indeed, studies on the molecular basis for the loss of CD28 are already providing information on methods to functionally rescue senescent T cells.

Section snippets

Persistent T-cell oligoclonality in chronic inflammation and persistent infection

Notwithstanding the complexity of the pathogenetic mechanisms underlying chronic inflammatory and autoimmune syndromes, many of these diseases are characterized by the accumulation of oligoclonal T cells. These cells have defined antigenic specificities, with each clone represented by a large number of cells with identical T-cell receptor (TCR) sequences. Oligoclonal T cells are found at the site of inflammation, but they can also pervade the peripheral circulation, resulting in global

Oligoclonal CD28null T cells: biological indicators of aging in the immune system

The recognition of an antigen by the TCR is a low-affinity interaction that is unable to sustain activation. Productive T-cell activation requires the coengagement of CD28, the most dominant costimulatory receptor, which principally serves to amplify the TCR signal [24], leading to various biological outcomes, such as T-cell proliferation and the production of soluble factors including interleukin (IL)-2 and interferon (IFN)-γ. Thus, CD28 is crucial to the induction and maintenance of

Senescent CD28null T cells are culprits of immune dysfunction: a new paradigm of disease pathogenesis

There is accumulating evidence that CD28null T cells are a common feature of inflammatory conditions such as RA [42], juvenile idiopathic arthritis [36], Wegener's granulomatosis [43], ankylosing spondylitis [44], atherosclerotic coronary artery disease (CAD) [10] and inflammatory bowel disease 45, 46. The occurrence of CD4+ CD28null T cells in RA and CAD is particularly interesting because the severity of clinical manifestations in both diseases is correlated with the abundance of these cells

Regulation of CD28 expression: molecular dissection of the program of T-cell senescence

Because CD28 is crucial to the induction of T cell-mediated immunity 24, 25, 26, the mechanism underlying the loss of CD28 expression during the proliferative life span of T cells is of particular interest. In vitro studies show that progressive downregulation of CD28 is tightly coupled to antigen-driven proliferation 54, 66. Molecular studies suggest that transcriptional silencing is the basic mechanism for the loss of CD28 during the replicative senescence of both CD4+ and CD8+ T cells (

T-cell senescence and the continuing challenge of disease management

Because of antigenic challenge throughout life and the impairment of T-cell production after birth, the T-cell pool is clearly susceptible to senescence. With chronic inflammation and persistent infection provoking continuous immune activation, accelerated T-cell senescence is unavoidable. How might this concept of premature senescence help in future disease management?

Data suggesting that patients with inflammatory disease have an overall reduced thymic output and prematurely aged T cells 16,

Concluding remarks

Chronic immune activation in inflammatory syndromes and persistent infections provides a milieu for accelerated replicative senescence of T cells. In many respects, these disease-associated oligoclonal T cells phenotypically and functionally resemble the senescent T cells that progressively accumulate during the normal course of aging. Key features of senescent T cells are their oligoclonality, longevity and acquisition of new phenotypes 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64.

Acknowledgements

Our research is supported by the Mayo Foundation, by Emory University, and by grants from the National Institutes of Health (R01-AG22379, R01-AG15043, R01-AR41974, R01-AR42527, R01-AI44142). We also thank James W. Fulbright for generating the figure, and Linda H. Arneson for secretarial support.

References (76)

  • C. Spaulding

    Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific stimulation

    Exp. Gerontol.

    (1999)
  • S. Gupta

    Effect of age on molecular signaling of TNF-α-induced apoptosis in human lymphocytes

    Mech. Ageing Dev.

    (2003)
  • C.M. Weyand

    Functional properties of CD4+ CD28 T cells in the aging immune system

    Mech. Ageing Dev.

    (1998)
  • D. Zhang

    Most antiviral CD8 T cells during chronic viral infection do not express high levels of perforin and are not directly cytotoxic

    Blood

    (2003)
  • M. Allez

    Expansion of CD8+ T cells with regulatory function after interaction with intestinal epithelial cells

    Gastroenterol

    (2002)
  • M.E. Paul

    Comparison of CD8+ T-cell subsets in HIV-infected rapid progressor children versus non-rapid progressor children

    J. Allergy Clin. Immunol.

    (2001)
  • A.N. Vallejo

    Functional disruption of the CD28 gene transcriptional initiator in senescent T cells

    J. Biol. Chem.

    (2001)
  • H.F. Valenzuela et al.

    Divergent telomerase and CD28 expression patterns in human CD4 and CD8 T cells following repeated encounters with the same antigenic stimulus

    Clin. Immunol.

    (2002)
  • A.N. Vallejo

    Molecular basis for the loss of CD28 expression in senescent T cells

    J. Biol. Chem.

    (2002)
  • G. Drewes et al.

    Global approaches to protein–protein interactions

    Curr. Opin. Cell Biol.

    (2003)
  • K.J. Warrington

    CD28 loss in senescent CD4+ T cells: Reversal by interleukin-12 stimulation

    Blood

    (2003)
  • T.J. Fry et al.

    Interleukin-7: From bench to clinic

    Blood

    (2002)
  • T.P. Arstila

    A direct estimate of the human αβ T cell receptor diversity

    Science

    (1999)
  • C.M. Weyand et al.

    T-cell responses in rheumatoid arthritis: Systemic abnormalities local disease

    Curr. Opin. Rheumatol.

    (1999)
  • L.R. Wedderburn

    Molecular fingerprinting reveals non-overlapping T cell oligoclonality between an inflamed site and peripheral blood

    Int. Immunol.

    (1999)
  • P.A. Fraser

    CD4 TCRBV CDR3 analysis in prevalent SLE cases from two ethnic groups

    Lupus

    (1999)
  • M. Shigematsu et al.

    Usage of T cell receptor (TCR) Vβ gene in ulcerative colitis

    J. Clin. Lab. Immunol.

    (1996)
  • H. Direskeneli

    Oligoclonal T cell expansions in patients with Behcet's disease

    Clin. Exp. Immunol.

    (1999)
  • I.J. Simpson

    Peripheral blood T lymphocytes in systemic vasculitis: increased T cell receptor Vβ2 gene usage in microscopic polyarteritis

    Clin. Exp. Immunol.

    (1995)
  • G. Liuzzo

    Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes

    Circulation

    (2000)
  • A. Lim

    Frequent contribution of T cell clonotypes with public TCR features to the chronic response against a dominant EBV-derived epitope: Application to direct detection of their molecular imprint on the human peripheral T cell repertoire

    J. Immunol.

    (2000)
  • F. Gambon-Deza

    Lymphocyte populations during tuberculosis infection: Vβ repertoires

    Infect. Immun.

    (1995)
  • K. Roessner

    Biased T-cell antigen receptor repertoire in Lyme arthritis

    Infect. Immun.

    (1998)
  • M.T. Fernandez-Mestre

    Analysis of the T-cell receptor β-chain variable-region (Vβ) repertoire in chronic Chagas' disease

    Tissue Antigens

    (2002)
  • U.G. Wagner

    Perturbation of the T cell repertoire in rheumatoid arthritis

    Proc. Natl. Acad. Sci. U. S. A.

    (1998)
  • M.P. Davenport

    Clonal selection, clonal senescence, and clonal succession: The evolution of the T cell response to infection with a persistent virus

    J. Immunol.

    (2002)
  • M.F. Doran

    Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study

    Arthritis Rheum.

    (2002)
  • Z. Bentwich

    Concurrent infections and HIV pathogenesis

    AIDS

    (2000)
  • Cited by (185)

    View all citing articles on Scopus
    View full text