Deficient Activity of the Nuclease MRE11A Induces T Cell Aging and Promotes Arthritogenic Effector Functions in Patients with Rheumatoid Arthritis

Li, Yinyin; Shen, Yi; Hohensinner, Philipp J.; Ju, Jihang; Wen, Zhenke; Goodman, Stuart B.; Zhang, Hui; Goronzy, Jörg J.; Weyand, Cornelia M.

doi:10.1016/j.immuni.2016.09.013

Cited by 95 publications

(93 citation statements)

References 57 publications

(64 reference statements)

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“…MRE11 inhibition in healthy T cells induced the aging phenotype, whereas MRE11 overexpression in rheumatoid arthritis T cells reverses it. The observation that the premature T cell aging is linked to MRE11 and telomere deprotection suggests MRE11 as a therapeutic target for immune aging and suppressing dysregulated inflammation (189). We expect that further knowledge of MRN biochemical mechanisms will be key to an improved understanding and intervention in multiple diseases including immune system aging.…”

Section: Mrn and Dysfunctional Telomeresmentioning

confidence: 99%

The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

Syed

Tainer

2018

Annu. Rev. Biochem.

324

345

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Genomic instability in disease and its fidelity in health depend on the DNA damage response (DDR), regulated in part from the complex of meiotic recombination 11 homolog 1 (MRE11), ATP-binding cassette–ATPase (RAD50), and phosphopeptide-binding Nijmegen breakage syndrome protein 1 (NBS1). The MRE11–RAD50–NBS1 (MRN) complex forms a multifunctional DDR machine. Within its network assemblies, MRN is the core conductor for the initial and sustained responses to DNA double-strand breaks, stalled replication forks, dysfunctional telomeres, and viral DNA infection. MRN can interfere with cancer therapy and is an attractive target for precision medicine. Its conformations change the paradigm whereby kinases initiate damage sensing. Delineated results reveal kinase activation, posttranslational targeting, functional scaffolding, conformations storing binding energy and en-abling access, interactions with hub proteins such as replication protein A (RPA), and distinct networks at DNA breaks and forks. MRN biochemistry provides prototypic insights into how it initiates, implements, and regulates multifunctional responses to genomic stress.

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Section: Mrn and Dysfunctional Telomeresmentioning

confidence: 99%

The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

Syed

Tainer

2018

Annu. Rev. Biochem.

324

345

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“…Early studies, utilizing measurements of telomeric length and clonal expansion of CD4 + CD28 − end-differentiated T cells, estimated that the immune aging process is accelerated by 2–3 decades in patients with RA as compared to age-matched controls (Fujii et al, 2009; Weyand et al, 2014). Molecular analysis of early CD4 + T cell responses in RA patients, modeled by activating CD4 + CD45RA + T cells and studying early effector cells, identified the nuclease MRE11A, the DNA-dependent protein kinase DNA-PKcs, and the cell cycle regulator ATM as molecular mediators of premature T cell aging (Li et al, 2016b; Shao et al, 2009, 2010). During adult life, MRE11A and ATM protein levels in CD4 + T cells gradually decline in healthy individuals.…”

Section: Maladaptive T Cell Aging: Promoter Of Tissue Inflammationmentioning

confidence: 99%

“…In RA CD4 + T cells, the lack of MRE11A nucleolytic activity is relevant for telomeric maintenance (Li et al, 2016b). MRE11A lo telomeres in RA T cells are coated by damage proteins and resemble uncapped, structurally abnormal telomeres.…”

Section: Maladaptive T Cell Aging: Promoter Of Tissue Inflammationmentioning

confidence: 99%

Successful and Maladaptive T Cell Aging

2017

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Throughout life, the T cell system adapts to shifting resources and demands, resulting in a fundamentally restructured immune system in older individuals. Here we review the cellular and molecular features of an aged immune system and discuss the trade-offs inherent to these adaptive mechanisms. Processes include homeostatic proliferation that maintains compartment size at the expense of partial loss in stemness and incomplete differentiation and the activation of negative regulatory programs, which constrain effector T cell expansion and prevent increasing oligoclonality but also interfere with memory cell generation. We propose that immune failure occurs when adaptive strategies developed by the aging T cell system fail and also discuss how, in some settings, the programs associated with T cell aging culminates in a maladaptive response that directly contributes to chronic inflammatory disease.

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“…Recent work has clarified the molecular underpinning of the accelerated aging phenotype of RA T-cells. Both, naïve and memory CD4 T-cells from RA patients have a defect in the activity of the nuclease MRE11A [48]. With evolutionarily highly conserved nuclease motifs, MRE11A has both exonuclease and endonuclease activity.…”

Section: Ra T-cells – Energy-deprived and Prematurely Oldmentioning

confidence: 99%

Metabolic signatures of T-cells and macrophages in rheumatoid arthritis

Weyand

Zeisbrich

Goronzy

2017

Current Opinion in Immunology

113

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In most autoimmune diseases, a decade-long defect in self-tolerance eventually leads to clinically relevant, tissue-destructive inflammatory disease. The pathogenic potential of chronic persistent immune responses during the pre-clinical and clinical phase is ultimately linked to the bioenergetic fitness of innate and adaptive immune cells. Chronic immune cell stimulation, high cellular turn-over, structural damage to the host tissue and maladaptive wound healing, all require a reliable supply of nutrients, oxygen, and biosynthetic precursors. Here, we use the model system of rheumatoid arthritis (RA) to discuss immunometabolism from the vantage point of T-cells and macrophages that encounter fundamentally different metabolic stress scenarios in the RA host. We outline the general principle that both insufficient nutrient supply, as well as nutrient excess generate cellular stress responses and guide immune function. ATPlow, NADPHhigh, ROSlow T-cells hyperproliferate and are forced into premature senescence. ATPhigh, ROShigh macrophages dimerize the glycolytic enzyme pyruvate kinase to amplify STAT3-dependent inflammatory effector functions. A corollary of this model is that simple nutraceutical interventions will be insufficient to re-educate the immune system in RA. Instead, interference with cell-type-exclusive and differentiation-stage-dependent metabolic setpoints will be needed to reprogram arthritogenic pathways.

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Deficient Activity of the Nuclease MRE11A Induces T Cell Aging and Promotes Arthritogenic Effector Functions in Patients with Rheumatoid Arthritis

Cited by 95 publications

References 57 publications

The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

Successful and Maladaptive T Cell Aging

Metabolic signatures of T-cells and macrophages in rheumatoid arthritis

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