Hallmarks of the aging T-cell system

Abstract

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 7th-10th 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. Age-associated 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.

Keywords: T-cell aging; T-cell differentiation; T-cell homeostasis; adaptive immunity; cellular senescence; immunosenescence.

Figure 1.. Naïve T cell homeostasis

A. Both, naïve CD4⁺ and naïve CD8⁺ T cells decrease in absolute numbers with age with the latter decreasing more drastically. B. Naïve T cell replenishment is maintained by thymic output and homeostatic proliferation in neonates. At age 20 years, thymic output has dropped to less than 20% with further decline to <1%; homeostatic proliferation accounts for the majority of naïve T cell generation throughout adulthood. C. The distribution of clonal sizes (illustrated by boxes) widens with age. Occurrences of larger clones in the naïve T cell compartment increase, associated with increased fitness selection over lifetime. D. The number of TCR in the T cell repertoire rapidly increases within the first decade of life and declines with older age. Computer simulations predict that the confidence interval of this decline is large.

Figure 2.. Fates of memory T cells with age

The antigen-specific memory T cells adopt several fates with age, including increase in NK cell-like TEMRA, short-lived effector memory T cells, exhausted T cells, decrease in stem-like memory T cells and decrease in tissue-residing T memory cells. Virtual memory T cells without prior experience of antigen encounter also increase with age.

Figure 3.. Molecular mechanisms underlying age-related naïve T cell functionality

Selected age-related changes at the cell surface and cytosolic level: TCR signaling is blunted with age through upregulation of DUSP6 due to loss of miR-181. Type I interferon response is weakened with age due to accumulation of SHP-1 at IFNα receptors (IFNAR). IL-2/STAT5 signaling is augmented with age due to the upregulation of CD25 aka IL-2 receptor α subunit (IL2R α). AKT/mTOR signaling is increased with age due to downregulation of PTEN by miR-21. At the nuclear level: In old T cells, chromatin accessibility shifts towards more differentiated states (illustrated by more opened chromatin) coupled with alterations in DNA methylation patterns. Transcription factors (TFs) driving effector differentiation such as BLIMP-1 increase with age due to upregulation of AKT/mTOR signaling and STAT5 signaling, whereas TFs driving memory and TFH differentiation such as TCF1 and BCL6 decline.

Figure 4.. Skewed differentiation of naïve T cells after antigen encounter

Naïve CD4⁺ T cells in older individuals tend to differentiate into short-lived effector T cells after antigen stimulation coupled with an impaired development of memory and TFH cells. This results in a curtailed memory population after infection or vaccination in older individuals. Mechanistically, the skewed differentiation is partially due to an early shift in transcription networks including upregulation of BATF, IRF4 and BLIMP-1 and loss of TCF1, FOXO1 and BCL6.