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