Editors' ChoiceAging

In aged hosts, T cells turn traitorous

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Science Translational Medicine  13 Jan 2021:
Vol. 13, Issue 576, eabg1759
DOI: 10.1126/scitranslmed.abg1759


Multimodal profiling of the aging immune system has identified highly abundant age–associated CD8+ T cells that home to organs and drive inflammation.

A hallmark of aging is gradual immune dysfunction, leading to maladaptive inflammation termed “inflammaging” and impairment of immune responses that may contribute to increased incidence of diseases such as cancer in the elderly. Changes described in the aging immune system are multifarious, but chief drivers of inflammaging have remained elusive.

Exploiting a panoply of single-cell sequencing technologies, Mogilenko et al. have greatly advanced these efforts by generating an index of the immune cells infiltrating the organs of young and old mice. The authors analyzed cells isolated from the spleen, peritoneum, lung, and liver, uncovering significant age-associated shifts in the proportions of many immune cell subsets. Most striking was a CD8+ T cell population detected exclusively in aged organs that exhibited high expression of the proinflammatory effector molecule granzyme K (GZMK) and markers of exhaustion. These CD8+ age–associated (Taa) cells were highly clonal and constituted nearly half of all circulating CD8+ T cells in aged mice. CD8+ Taa cells also highly expressed integrin α4 (CD49d), which likely mediated infiltration of organs. There, the GZMK produced by these cells appeared to provoke stromal cells to adopt the so-called senescence-associated secretory phenotype (SASP), a pathogenic proinflammatory state that fuels inflammaging. Turning to humans, Mogilenko et al. analyzed peripheral blood mononuclear cells from healthy, non-obese adults in their third versus seventh decades. This again revealed a population of GZMK+ CD8+ T cells that increased with age, including a subset of highly clonal T effector memory cells that seemed to rely on the same transcription factors as did mouse CD8+ Taa cells. Thus, a similar paradigm appears to be at play in humans.

Several questions remain. Studies involving transfer of CD8+ T cells between young and aged mice indicated that the signals driving emergence of GZMK+ CD8+ T cells were cell-extrinsic, imposed by the aged host environment. However, the identity of these signals–and whether they are conserved in humans–is still unknown. Finally, it is also not yet clear whether GZMK+ CD8+ T cells are themselves sufficient to promote the SASP and inflammaging. Determining this will inform the therapeutic value of targeting this population.

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