DNA damage, metabolism and aging in pro-inflammatory T cells: Rheumatoid arthritis as a model system

Abstract

The aging process is the major driver of morbidity and mortality, steeply increasing the risk to succumb to cancer, cardiovascular disease, infection and neurodegeneration. Inflammation is a common denominator in age-related pathologies, identifying the immune system as a gatekeeper in aging overall. Among immune cells, T cells are long-lived and exposed to intense replication pressure, making them sensitive to aging-related abnormalities. In successful T cell aging, numbers of naïve cells, repertoire diversity and activation thresholds are preserved as long as possible; in maladaptive T cell aging, protective T cell functions decline and pro-inflammatory effector cells are enriched. Here, we review in the model system of rheumatoid arthritis (RA) how maladaptive T cell aging renders the host susceptible to chronic, tissue-damaging inflammation. In T cells from RA patients, known to be about 20years pre-aged, three interconnected functional domains are altered: DNA damage repair, metabolic activity generating energy and biosynthetic precursor molecules, and shaping of plasma membranes to promote T cell motility. In each of these domains, key molecules and pathways have now been identified, including the glycolytic enzymes PFKFB3 and G6PD; the DNA repair molecules ATM, DNA-PKcs and MRE11A; and the podosome marker protein TKS5. Some of these molecules may help in defining targetable pathways to slow the T cell aging process.

Keywords: ATM; DNA damage responses; DNA-PKcs; Inflammation; MRE11A; Rheumatoid arthritis; T cell aging; Telomere; mtDNA.

Figure 1. Healthy and Maladaptive T Cell Aging

T cells from patients with the inflammatory syndrome rheumatoid arthritis (RA) age at an accelerated pace. Naïve CD4 T cells from RA patients are metabolically reprogrammed. Due to suppressed glycolysis, they produce less ATP and shunt glucose into the pentose phosphate pathway, yielding high levels of NADPH and low levels of reactive oxygen species (ROS). One outcome is increased lipogenesis, lipid droplet formation, membrane ruffling and accelerated T cell motility. A second outcome is insufficient activation of the DNA repair machinery, affecting the kinase ATM and the nuclease MRE11A. As a consequence, telomeres are uncapped and T cells enter the senescence program. Aged T cells express CD57 and upregulate p16 and p21. Damaged telomeres and membrane podosome formation enable T cells to invade into the synovial tissue and cause chronic synovitis. RA T cells serve as a model system to explore the aging process in healthy T cells, in which phenotypes are less pronounced but molecular mechanisms may be shared.

Figure 2. Functional Domains affected by low ATM Activity

The serine/threonine kinase Ataxia Telangiectasia Mutated (ATM) belongs to the superfamily of phosphatidylinositol 3-kinase-related kinases and is recognized as an activator of the DNA damage response and a coordinator of cell cycle progression and DNA repair. ATM function is redox sensitive, connecting metabolic activity with the DNA repair machinery. In ATM^low cells, mitochondrial oxidative phosphorylation is low, damaged DNA accumulates, and sensing of cytoplasmic DNA fragments is inadequate. Humans born homozygous for mutated ATM age prematurely, are predisposed to cancer and early cardiovascular disease. ATM^low T cells in RA patients promote tissue inflammation.

Figure 3. Functional consequences of MRE11A deficiency

MRE11A complexes with RAD50 and NBS1 to form the MRN complex, required for homologous recombination and DNA repair. MRE11A contributes single-strand endonuclease activity and double-strand–specific 3′-5′ exonuclease activity. The MRE11A partner RAD50 may be responsible for binding of DNA ends and avoiding end degradation by regulating MRE11’s nucleolytic activity. Hypomorphic mutations of MRE11A lead to an ataxia-telangiectasia–like disorder (A-TLD). In human T cells, MRE11A preferentially localizes to telomeric ends, to prevent uncapping and instability and also regulates heterochromatin unraveling. MRE11A^low T cells appear to phenocopy ATM^low T cells, are hypermobile, tissue-invasive and sustain tissue-damaging inflammation.

Figure 4. Telomere Attrition in T Cell Aging

Telomeric shortening, eliciting a “telomeric crisis”, is recognized as a fundamental mechanism of inducing cellular senescence. However, human T cells maintain telomeric sequences >5,000 kb, and do not enter cellular senescence; raising the question whether loss of telomeric sequences contributes to T cell aging. T cell aging has been associated with telomeric uncapping and insufficient telomeric repair. Specifically, the nuclease MRE11A protects from uncapping and promotes telomeric repair. Theoretically, defects in the function of shelterin proteins could also contribute to T cell aging, but this is insufficiently explored.