The immune system is a fortress, defending the body against the constant threat of invasion by bacteria, viruses and other microorganisms. This protection is lifelong: immune cells remain vigilant for infectious agents that we may have encountered, naturally or through vaccinations, decades ago.
T cells are responsible for keeping track of these pathogenic encounters by differentiating and dividing into specialized subpopulations. “This generates a pool of memory T cells which can recognize the same antigen when it reappears later in life. They comprise the memory of the immune system,” explains Anis Larbi, a Principal Investigator at A*STAR’s Singapore Immunology Network (SIgN) and a co-corresponding author of this study.
With age, however, cracks appear in the immunological armor; elderly individuals cannot respond to immune challenges as robustly as before. To uncover the mechanisms behind the phenomenon of immune-aging, Larbi led a team of researchers to probe a recently discovered subset of memory T cells, called stem cell memory T lymphocytes (TSCM). Could a drop in the self-renewal capacity of TSCM explain why seniors are more susceptible to complications following infections?
Larbi’s team, in collaboration with Tze Pin Ng at the National University Health System (NUHS) and international collaborators from Italy, Malaysia, Spain and Germany, used a combination of technologies to piece this puzzle together, one cell at a time.
With high-dimensional flow cytometry, the team panned heterogeneous populations of T cells to pick out TSCM based on their molecular signature. They then characterized these TSCM using biomarkers of senescence and aging, isolating samples of TSCM from elderly Singaporeans. Next, single-cell RNA sequencing allowed the researchers to accurately define subsets of these aged T cells based on their RNA profile and investigate how RNA signatures may be altered in aging.
Their findings confirmed that with aging, TSCM populations take a nosedive. The root causes of this were revealed to be two-fold: chronic inflammation contributed to their decline while disruption in the Wnt/β-catenin pathway in TSCM precursor cells affected their downstream development.
“We have shown that maintaining early precursors, the naïve T cells, is an important aspect to sustain immunity in older age,” Larbi said. “As inflamm-aging is observed in conjunction with a drop in numbers and quality of TSCM, better controlling the inflammatory process in older age may boost the functional capacity of TSCM, to rejuvenate memory T cell responses.”
According to the scientists, both pathways can be leveraged as potential therapeutic targets to reverse immune-related aging. Ongoing studies are focused on tracking development versus the early onset of senescence in T cells, with the view of developing more effective vaccines and immunotherapies for the elderly. TSCM function and diversity may also be restored through the calibrated use of Wnt/β-catenin agonists, they propose.
The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN).
