FOXO1 deficiency impairs proteostasis in aged T cells

Jin, Jun; Li, Xuanying; Hu, Bin; Kim, Chulwoo; Cao, Wenqiang; Zhang, Huimin; Weyand, Cornelia M.; Goronzy, Jörg J.

doi:10.1126/sciadv.aba1808

Cited by 38 publications

(58 citation statements)

References 46 publications

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“…112 In parallel, prolonged activation of AKT results in sustained FOXO1 degradation that impairs the functional activity of lysosomes resulting in impaired proteostasis and the production of B-cell-toxic exosomes. 113 In addition, effector-like T cells express higher levels of the ATPase CD39, and CD39 levels on activated CD4 T cells inversely correlate with the development of influenza-specific memory T-cell responses. 24 Moreover, adenosine generated by CD39 from secreted ATP inhibited TFH development, through negative regulation by BCL6.…”

Section: Age-related Defects In Naive T Cells That Affect Primary Vacmentioning

confidence: 99%

Influence of immune aging on vaccine responses

Gustafson

Kim

Weyand

et al. 2020

Journal of Allergy and Clinical Immunology

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229

177

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Impaired vaccine responses in older individuals are associated with alterations in both the quantity and quality of the T-cell compartment with age. As reviewed herein, the T-cell response to vaccination requires a fine balance between the generation of inflammatory effector T cells versus follicular helper T (T FH) cells that mediate high-affinity antibody production in tandem with the induction of longlived memory cells for effective recall immunity. During aging, we find that this balance is tipped where T cells favor short-lived effector but not memory or T FH responses. Consistently, vaccine-induced antibodies commonly display a lower protective capacity. Mechanistically, multiple, potentially targetable, changes in T cells have been identified that contribute to these age-related defects, including posttranscription regulation, T-cell receptor signaling, and metabolic function. Although research into the induction of tissue-specific immunity by vaccines and with age is still limited, current mechanistic insights provide a framework for improved design of age-specific vaccination strategies that require further evaluation in a clinical setting. (

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Section: Age-related Defects In Naive T Cells That Affect Primary Vacmentioning

confidence: 99%

Influence of immune aging on vaccine responses

Gustafson

Kim

Weyand

et al. 2020

Journal of Allergy and Clinical Immunology

Self Cite

229

177

View full text Add to dashboard Cite

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“…All rights reserved (167). Another feature that routes old naïve T cells to a more effector-like state after activation is the skewed distribution of cellular organelles, manifested as downregulated lysosome biogenesis coupled with expansion of multivesicular bodies due to a failure to restore FOXO1 expression (168).…”

Section: Accepted Articlementioning

confidence: 99%

Hallmarks of the aging T‐cell system

2021

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The adaptive immune system has the enormous challenge to protect the host through the generation and differentiation of pathogen-specific short-lived effector T cells while in parallel developing long-lived memory cells to control future encounters with the same pathogen. A complex regulatory network is needed to preserve a population of naïve cells over lifetime that exhibit sufficient diversity of antigen receptors to respond to new antigens, while also sustaining immune memory. In parallel, cells need to maintain their proliferative potential and the plasticity to differentiate into different functional lineages. Initial signs of waning immune competence emerge after 50 years of age, with increasing clinical relevance in the 7 th-10 th decade of life. Morbidity and mortality from infections increase, as drastically exemplified by the current COVID-19 pandemic. Many vaccines, such as for the influenza virus, are poorly effective to generate protective immunity in older individuals. Ageassociated changes occur at the level of the T cell population as well as the functionality of its cellular constituents. The system highly relies on the self-renewal of naïve and memory T cells, which is robust but eventually fails. Genetic and epigenetic modifications contribute to functional differences in responsiveness and differentiation potential. To some extent, these changes arise from defective maintenance; to some, they represent successful, but not universally beneficial adaptations to the aging host. Interventions that can compensate for the age-related defects and improve immune responses in older adults are increasingly within reach.

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“…FOXO1 is highly expressed in naïve T cells and downregulated after priming concomitant with the activation of AKT. During effector differentiation, FOXO1 expression was partially restored in young T cells, whereas differentiating old T cells had significantly less FOXO1, at least in part, due to sustained AKT activation [115]. FOXO1 is one of the transcription factors critical for the generation of memory CD8 T cells by repressing T-BET expression and promoting EOMES expression [45,46].…”

Section: Tcf1 In T Cell Agingmentioning

confidence: 99%

“…Given that FOXO1 also regulates gene expression associated with cell survival [114], the precise contribution of FOXO1 to the differentiation of aged T cells remains to be determined. Interestingly, loss of FOXO1 activity is associated with the accumulation of short isoforms of TCF1 lacking the β-catenin binding domain [115]. Unlike functioning as presumptive dominant-negative regulators, TCF1 short isoforms were sufficient to support T cell maturation in the thymus [117] and memory CD8 T cell generation after acute infection [28], with long isoforms still needed for thymocyte survival and development of central memory phenotypes.…”

Section: Tcf1 In T Cell Agingmentioning

confidence: 99%

The Transcription Factor TCF1 in T Cell Differentiation and Aging

Kim

Jin

Weyand

et al. 2020

IJMS

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The transcription factor T cell factor 1 (TCF1), a pioneer transcription factor as well as a downstream effector of WNT/β-catenin signaling, is indispensable for T cell development in the thymus. Recent studies have highlighted the additional critical role of TCF1 in peripheral T cell responses to acute and chronic infections as well as cancer. Here, we review the regulatory functions of TCF1 in the differentiation of T follicular helper cells, memory T cells and recently described stem-like exhausted T cells, where TCF1 promotes less differentiated stem-like cell states by controlling common gene-regulatory networks. These studies also provide insights into the mechanisms of defective T cell responses in older individuals. We discuss alterations in TCF1 expression and related regulatory networks with age and their consequences for T cell responses to infections and vaccination. The increasing understanding of the pathways regulating TCF1 expression and function in aged T cells holds the promise of enabling the design of therapeutic interventions aiming at improving T cell responses in older individuals.

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FOXO1 deficiency impairs proteostasis in aged T cells

Cited by 38 publications

References 46 publications

Influence of immune aging on vaccine responses

Influence of immune aging on vaccine responses

Hallmarks of the aging T‐cell system

The Transcription Factor TCF1 in T Cell Differentiation and Aging

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