DNA-dependent protein kinase catalytic subunit mediates T-cell loss in rheumatoid arthritis

Department of Medicine, Immunology and Rheumatology, Stanford University, Stanford, CA, USA.
EMBO Molecular Medicine (Impact Factor: 8.67). 10/2010; 2(10):415-27. DOI: 10.1002/emmm.201000096
Source: PubMed


In the autoimmune syndrome rheumatoid arthritis (RA), T cells and T-cell precursors have age-inappropriate shortening of telomeres and accumulate deoxyribonucleic acid (DNA) double strand breaks. Whether damaged DNA elicits DNA repair activity and how this affects T-cell function and survival is unknown. Here, we report that naïve and resting T cells from RA patients are susceptible to undergo apoptosis. In such T cells, unrepaired DNA stimulates a p53-ataxia telangiectasia mutated-independent pathway involving the non-homologous-end-joining protein DNA-protein kinase catalytic subunit (DNA-PKcs). Upregulation of DNA-PKcs transcription, protein expression and phosphorylation in RA T cells co-occurs with diminished expression of the Ku70/80 heterodimer, limiting DNA repair capacity. Inhibition of DNA-PKcs kinase activity or gene silencing of DNA-PKcs protects RA T cells from apoptosis. DNA-PKcs induces T-cell death by activating the JNK pathway and upregulating the apoptogenic BH3-only proteins Bim and Bmf. In essence, in RA, the DNA-PKcs-JNK-Bim/Bmf axis transmits genotoxic stress into shortened survival of naïve resting T cells, imposing chronic proliferative turnover of the immune system and premature immunosenescence. Therapeutic blockade of the DNA-PK-dependent cell-death machinery may rejuvenate the immune system in RA.

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Available from: Cornelia M Weyand,
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    • "In con­ trast, lymphopenia has been implicated in triggering auto­ immunity, possibly through the selection of autoreactive T cell clones in a host that favors autoproliferation to fill an empty space (King et al., 2004; Goronzy and Weyand, 2012, 2013). The signals inducing T cell death in RA patients are multifold, including insufficiency of telomerase (Fujii et al., 2009), lack of DNA damage repair (Shao et al., 2009), and activation of JNK stress kinases (Shao et al., 2010). The current study adds energy deprivation as well as dysbalanced ROS consumption to the signals that deplete T cells in RA. "
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    ABSTRACT: In the HLA class II-associated autoimmune syndrome rheumatoid arthritis (RA), CD4 T cells are critical drivers of pathogenic immunity. We have explored the metabolic activity of RA T cells and its impact on cellular function and fate. Naive CD4 T cells from RA patients failed to metabolize equal amounts of glucose as age-matched control cells, generated less intracellular ATP, and were apoptosis-susceptible. The defect was attributed to insufficient induction of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a regulatory and rate-limiting glycolytic enzyme known to cause the Warburg effect. Forced overexpression of PFKFB3 in RA T cells restored glycolytic flux and protected cells from excessive apoptosis. Hypoglycolytic RA T cells diverted glucose toward the pentose phosphate pathway, generated more NADPH, and consumed intracellular reactive oxygen species (ROS). PFKFB3 deficiency also constrained the ability of RA T cells to resort to autophagy as an alternative means to provide energy and biosynthetic precursor molecules. PFKFB3 silencing and overexpression identified a novel extraglycolytic role of the enzyme in autophagy regulation. In essence, T cells in RA patients, even those in a naive state, are metabolically reprogrammed with insufficient up-regulation of the glycolytic activator PFKFB3, rendering them energy-deprived, ROS- and autophagy-deficient, apoptosis-sensitive, and prone to undergo senescence.
    Journal of Experimental Medicine 09/2013; 210(10). DOI:10.1084/jem.20130252 · 12.52 Impact Factor
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    • "DNA-PKcs influences intracellular signaling pathways through at least two mechanisms. It activates the inflammasome and increases NFκB activity; and it activates the stress kinase JNK pathway (Rajagopalan et al., 2010; Shao et al., 2010). Both pathways can contribute to the production of inflammatory cytokines. "
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    ABSTRACT: Immune aging is best known for its immune defects that increase susceptibility to infections and reduce adaptive immune responses to vaccination. In parallel, the aged immune system is prone to autoimmune responses and many autoimmune diseases increase in incidence with age or are even preferentially encountered in the elderly. Why an immune system that suboptimally responds to exogenous antigen fails to maintain tolerance to self-antigens appears to be perplexing. In this review, we will discuss age-associated deviations in the immune repertoire and the regulation of signaling pathways that may shed light on this conundrum.
    Frontiers in Immunology 06/2013; 4:131. DOI:10.3389/fimmu.2013.00131
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    • "Forced overexpression of ATM restores the ability to repair fragmented DNA and extends the life span of RA T cells. RA T cells sense that they fail to fix DNA damage and chronically activate cell internal stress pathways [24,25]. It is currently unknown how these molecular networks are regulated in patients who have GCA. "
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    ABSTRACT: Susceptibility for giant cell arteritis increases with chronological age, in parallel with age-related restructuring of the immune system and age-induced remodeling of the vascular wall. Immunosenescence results in shrinkage of the naïve T-cell pool, contraction of T-cell diversity, and impairment of innate immunity. Aging of immunocompetent cells forces the host to take alternative routes for protective immunity and confers risk for pathogenic immunity that causes chronic inflammatory tissue damage. Dwindling immunocompetence is particularly relevant as the aging host is forced to cope with an ever growing infectious load. Immunosenescence coincides with vascular aging during which the arterial wall undergoes dramatic structural changes and medium and large arteries lose their pliability and elasticity. On the molecular level, elastic fibers deteriorate and matrix proteins accumulate biochemical modifications. Thus, the aging process impacts the two major biologic systems that liaise to promote giant cell arteritis; the immune system and the vessel wall niche.
    Arthritis research & therapy 08/2011; 13(4):231. DOI:10.1186/ar3358 · 3.75 Impact Factor
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