T cell fate decisions during memory cell generation with aging

Sturmlechner, Ines; Jain, Abhinav K.; Mu, Yunmei; Weyand, Cornelia M.; Goronzy, Jörg J.

doi:10.1016/j.smim.2023.101800

Cited by 7 publications

(3 citation statements)

References 107 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, this is not always the case; we have shown that the initial expansion of antigen-specific T cells after Zostavax vaccination is independent of age, while the contraction in frequencies after peak responses is more severe in older adults, likely due to increasing DNA damage and replicative stress responses (3,4). We have recently reviewed the mechanisms underlying this impaired generation of long-lived memory T cells in older adults (5). Equally important is the question how long memory T cells live and how well their functionality is maintained into older age.…”

Section: Introductionmentioning

confidence: 98%

Heterogeneity of memory T cells in aging

Jain,

Sturmlechner,

Weyand

et al. 2023

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 98%

Heterogeneity of memory T cells in aging

Jain,

Sturmlechner,

Weyand

et al. 2023

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Novel T cells expressing unique T cell receptors (TCRs) are exclusively generated in the thymus; however, thymic output already declines in late childhood and particularly during puberty; the bulk of T cell generation during the adult lifetime derives from division of existing peripheral T cells. 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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Moreover, during aging T cell memory is severely impaired 6,7 , and senescent CD8 + T cell subsets that exhibit DNA damage, cell cycle arrest, mitochondrial dysfunction due to defective mitophagy 8 , and global poor effector function accumulate [9][10][11] . Amongst the cellular processes that benefit the formation and maintenance of memory CD8 + T cells but which are negatively impacted by ageing 6,12,13 , there are two highly conserved mechanisms: macroautophagy (hereafter termed autophagy) and asymmetric cell division (ACD).…”

Section: Introductionmentioning

confidence: 99%

Inheritance of old mitochondria controls early CD8⁺T cell fate commitment and is regulated by autophagy

Borsa,

Lechuga-Vieco,

Kayvanjoo

et al. 2024

Preprint

View full text Add to dashboard Cite

T cell immunity is impaired during ageing, particularly in memory responses needed for efficient vaccination. Autophagy and asymmetric cell division (ACD) are cell biological mechanisms key to memory formation, which undergo a decline upon ageing. However, despite the fundamental importance of these processes in cellular function, the link between ACD and in vivo fate decisions has remained highly correlative in T cells and in the field of mammalian ACD overall. Here we provide robust causal evidence linking ACD to in vivo T cell fate decisions and our data are consistent with the concept that initiation of asymmetric T cell fates is regulated by autophagy. Analysing the proteome of first-daughter CD8+T cells following TCR-triggered activation, we reveal that mitochondrial proteins rely on autophagy for their asymmetric inheritance and that damaged mitochondria are polarized upon first division. These results led us to evaluate whether mitochondria were asymmetrically inherited and to functionally address their impact on T cell fate. For this we used a novel mouse model that allows sequential tagging of mitochondria in mother and daughter cells, enabling their isolation and subsequent in vivo analysis of CD8+T cell progenies based on pre-mitotic cell cargo. Autophagy-deficient CD8+T cells showed impaired clearance and symmetric inheritance of old mitochondria, suggesting that degradation events promote asymmetry and are needed to generate T cells devoid of old organelles. Daughter cells inheriting old mitochondria are more glycolytic and upon adoptive transfer show reduced memory potential, whereas daughter cells that have not inherited old mitochondria from the mother cell are long-lived and expand upon cognate-antigen challenge. Proteomic and single-cell transcriptomic analysis of cells inheriting aged mitochondria suggest that their early fate divergence relies on one carbon metabolism as a consequence of poor mitochondrial quality and function. These findings increase our understanding of how T cell diversity is early-imprinted during division and will help foster the development of strategies to modulate T cell function.

show abstract

T cell fate decisions during memory cell generation with aging

Cited by 7 publications

References 107 publications

Heterogeneity of memory T cells in aging

Heterogeneity of memory T cells in aging

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

Inheritance of old mitochondria controls early CD8⁺T cell fate commitment and is regulated by autophagy

Contact Info

Product

Resources

About

T cell fate decisions during memory cell generation with aging

Cited by 7 publications

References 107 publications

Heterogeneity of memory T cells in aging

Heterogeneity of memory T cells in aging

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

Inheritance of old mitochondria controls early CD8+T cell fate commitment and is regulated by autophagy

Contact Info

Product

Resources

About

Inheritance of old mitochondria controls early CD8⁺T cell fate commitment and is regulated by autophagy