TRIB2 safeguards naive T cell homeostasis during aging

Cao, Wenqiang; Sturmlechner, Ines; Zhang, Huimin; Jin, Jun; Hu, Bin; Jadhav, Rohit R.; Fang, Fengqin; Weyand, Cornelia M.; Goronzy, Jörg J.

doi:10.1016/j.celrep.2023.112195

Cited by 9 publications

(8 citation statements)

References 61 publications

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“…Decreased IL-7 receptor expression on aged T cells and less accessibility to secondary lymph organs contribute to the loss of naïve T cells with age ( 51 , 52 ). Besides, due to declined TRIB2, aged naïve T cells are prone to differentiation towards memory response to homeostatic cytokines that further contribute to the loss of naïve T cells ( 53 ).…”

Section: Naïve/memory T Cells Imbalance and Admentioning

confidence: 99%

“…More specific inventions are required to investigate the impact of naïve cells on AD. TRIB2 is a vital regulator of naivety, and its stabilizing drugs have been applied to clinical treatment ( 53 ). It is thus of great interest to evaluate the effect of TRIB2-mediated maintenance of naïve T cells to AD.…”

Section: Naïve/memory T Cells Imbalance and Admentioning

confidence: 99%

“…CD4 T cells also acquire NK receptors and become cytotoxic with age, possibly associated with downregulated ThPOK ( 7 , 76 , 77 ). ThPOK expression declines in aged CD4 T cells ( 53 ). Thus, ThPOK may play a crucial role in accumulating senescent T cells.…”

Section: Senescent T Cells and Admentioning

confidence: 99%

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T cell aging and Alzheimer’s disease

Guo

Gould³

et al. 2023

Front. Immunol.

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The brain has long been considered an immune-privileged organ due to the presence of the blood-brain barrier (BBB). However, recent discoveries have revealed the underestimated role of T cells in the brain through the meningeal lymphatic system. Age is the primary risk factor for Alzheimer’s disease (AD), resulting in marked age-dependent changes in T cells. Manipulating peripheral T cell immune response has been shown to impact AD, but the relationship between T cell aging and AD remains poorly understood. Given the limited success of targeting amyloid beta (Aβ) and the growing evidence of T cells’ involvement in non-lymphoid organ aging, a deeper understanding of the relationship between T cells and AD in the context of aging is crucial for advancing therapeutic progress. In this review, we comprehensively examine existing studies on T cells and AD and offer an integrated perspective on their interconnections in the context of aging. This understanding can inform the development of new interventions to prevent or treat AD.

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Section: Naïve/memory T Cells Imbalance and Admentioning

confidence: 99%

Section: Naïve/memory T Cells Imbalance and Admentioning

confidence: 99%

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T cell aging and Alzheimer’s disease

Guo

Gould³

et al. 2023

Front. Immunol.

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“…However, CD4 + T cells are protected from end-differentiation for many years. One underlying mechanism for CD4 + T cells to eventually lose this state of youthfulness and convert to TEMRA with older age is the loss of homeostatic quiescence involving the lineage-determining transcription factors ThPOK and RUNX3 that regulate the expression of TRIB2 (32). A subset of CD4 + T cells lose ThPOK and TRIB2, while gaining RUNX3 expression with age.…”

Section: Increased Vulnerability Of Cd8 + T Cells To Age-associated C...mentioning

confidence: 99%

Heterogeneity of memory T cells in aging

Jain,

Sturmlechner,

Weyand

et al. 2023

Front. Immunol.

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Immune memory is a requisite and remarkable property of the immune system and is the biological foundation of the success of vaccinations in reducing morbidity from infectious diseases. Some vaccines and infections induce long-lasting protection, but immunity to other vaccines and particularly in older adults rarely persists over long time periods. Failed induction of an immune response and accelerated waning of immune memory both contribute to the immuno-compromised state of the older population. Here we review how T cell memory is influenced by age. T cell memory is maintained by a dynamic population of T cells that are heterogeneous in their kinetic parameters under homeostatic condition and their function. Durability of T cell memory can be influenced not only by the loss of a clonal progeny, but also by broader changes in the composition of functional states and transition of T cells to a dysfunctional state. Genome-wide single cell studies on total T cells have started to provide insights on the influence of age on cell heterogeneity over time. The most striking findings were a trend to progressive effector differentiation and the activation of pro-inflammatory pathways, including the emergence of CD4+ and CD8+ cytotoxic subsets. Genome-wide data on antigen-specific memory T cells are currently limited but can be expected to provide insights on how changes in T cell subset heterogeneity and transcriptome relate to durability of immune protection.

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“…It has been estimated that less than 20% of T cell generation already in young adults is of thymic origin, which further declines to 1% or less in older adults ( 4 , 5 ). Remarkably, mechanisms maintaining a naive CD4 + T cell compartment are very effective in contrast with naive CD8 + T cells ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

PREX1 improves homeostatic proliferation to maintain a naïve CD4 T cell compartment in older age

Zhang,

Okuyama,

Jain

et al. 2024

JCI Insight

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The human adult immune system maintains normal T cell counts and compensates for T cell loss throughout life, mainly through peripheral homeostatic proliferation after the ability of the thymus to generate new T cells has rapidly declined at adolescence. This process is mainly driven by STAT5-activating cytokines, most importantly IL-7, and is very effective in maintaining a large naive CD4 + T cell compartment into older age. Here, we describe that naive CD4 + T cells undergo adaptations to optimize IL-7 responses by upregulating the guanine-nucleotide exchange factor PREX1 in older age. PREX1 promotes nuclear translocation of phosphorylated STAT5, thereby supporting homeostatic proliferation in response to IL-7. Through the same mechanism, increased expression of PREX1 also biases naive cells to differentiate into effector T cells. These findings are consistent with the concept that primarily beneficial adaptations during aging, i.e., improved homeostasis, account for unfavorable functions of the aged immune system, in this case biased differentiation.

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TRIB2 safeguards naive T cell homeostasis during aging

Cited by 9 publications

References 61 publications

T cell aging and Alzheimer’s disease

T cell aging and Alzheimer’s disease

Heterogeneity of memory T cells in aging

PREX1 improves homeostatic proliferation to maintain a naïve CD4 T cell compartment in older age

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