Characterisation of distinct senescent-like T cell populations during healthy and unhealthy ageing

Abstract Ageing is accompanied by progressive remodelling of the immune system, but chronic metabolic disease may accelerate this process and drive qualitatively distinct forms of immune dysfunction. Here, we used type 2 diabetes (T2D) as a model of unhealthy immune ageing to identify a distinct population of CD8 + T EMRA cells that accumulates in older individuals with T2D. These cells were highly differentiated, oligoclonally expanded and had shorter telomeres, consistent with an increased replicative history and premature senescence-like state. Unlike conventional T EMRA cells, which can preserve cytotoxic function through acquisition of NK-cell receptors, T2D-associated T EMRA cells showed reduced surface expression of KLRG1, NKG2D and NKG2A together with defective receptor recycling. TGFβ1 was elevated in T2D and reproduced several features of this phenotype in vitro, including increased T EMRA differentiation, reduced NK-receptor expression, altered receptor trafficking and induction of p21. Functionally, these cells displayed reduced TCR-triggered degranulation, correlating with impaired cytotoxicity and altered tissue distribution in individuals with T2D. Rather than providing effective immune surveillance, the accumulation of these highly differentiated T EMRA cells with diminished effector capacity may compromise immune function. Together, these findings identify a distinct senescent-like CD8 + T EMRA state linking metabolic inflammation to dysregulated T cell differentiation.