Elizabeth C. Carroll

Summary Cellular senescence is accompanied by a senescence‐associated secretory phenotype ( SASP ). We show here that primary human senescent CD 8 + T cells also display a SASP comprising chemokines, cytokines and extracellular matrix remodelling proteases that are unique to this subset and contribute to age‐associated inflammation. We found the CD 8 + CD 45 RA + CD 27 − EMRA subset to be the most heterogeneous, with a population aligning with the naïve T cells and another with a closer association to the effector memory subset. However, despite the differing processes that give rise to these senescent CD 8 + T cells once generated, they both adopt a unique secretory profile with no commonality to any other subset, aligning more closely with senescence than quiescence. Furthermore, we also show that the SASP observed in senescent CD 8 + T cells is governed by p38 MAPK signalling.

Abstract The susceptibility of human CD4 + and CD8 + T cells to senesce differs, with CD8 + T cells acquiring an immunosenescent phenotype faster than the CD4 + T cell compartment. We show here that it is the inherent difference in mitochondrial content that drives this phenotype, with senescent human CD4 + T cells displaying a higher mitochondrial mass. The loss of mitochondria in the senescent human CD8 + T cells has knock‐on consequences for nutrient usage, metabolism and function. Senescent CD4 + T cells uptake more lipid and glucose than their CD8 + counterparts, leading to a greater metabolic versatility engaging either an oxidative or a glycolytic metabolism. The enhanced metabolic advantage of senescent CD4 + T cells allows for more proliferation and migration than observed in the senescent CD8 + subset. Mitochondrial dysfunction has been linked to both cellular senescence and aging; however, it is still unclear whether mitochondria play a causal role in senescence. Our data show that reducing mitochondrial function in human CD4 + T cells, through the addition of low‐dose rotenone, causes the generation of a CD4 + T cell with a CD8 + ‐like phenotype. Therefore, we wish to propose that it is the inherent metabolic stability that governs the susceptibility to an immunosenescent phenotype.

Type 2 diabetes is a global health priority, given that it is driven, in part, by an ageing population, the role of immune senescence has been overlooked. This is surprising, as the functional impairments of senescent T cells show strong similarities to patients with hyperglycaemia. Immune senescence is typified by alterations in T cell memory, such as the accumulation of highly differentiated end-stage memory T cells, as well as a constitutive low-grade inflammation, which drives further immune differentiation. We show here in a preliminary study that people living with type 2 diabetes have a higher circulating volume of senescent T cells accompanied with a higher level of systemic inflammation. This inflammatory environment drives the expression of a unique array of chemokine receptors on senescent T cells, most notably C-X-C motif chemokine receptor type 2. However, this increased expression of migratory markers does not translate to improved extravasation owing to a lack of glucose uptake by the T cells. Our results therefore demonstrate that the presence of senescent T cells has a detrimental impact on immune function during type 2 diabetes.

Humans that are heterozygous for the common S180L polymorphism in the Toll-like receptor (TLR) adaptor Mal (encoded by TIRAP) are protected from a number of infectious diseases, including tuberculosis (TB), whereas those homozygous for the allele are at increased risk. The reason for this difference in susceptibility is not clear. We report that Mal has a TLR-independent role in interferon-gamma (IFN-γ) receptor signaling. Mal-dependent IFN-γ receptor (IFNGR) signaling led to mitogen-activated protein kinase (MAPK) p38 phosphorylation and autophagy. IFN-γ signaling via Mal was required for phagosome maturation and killing of intracellular Mycobacterium tuberculosis (Mtb). The S180L polymorphism, and its murine equivalent S200L, reduced the affinity of Mal for the IFNGR, thereby compromising IFNGR signaling in macrophages and impairing responses to TB. Our findings highlight a role for Mal outside the TLR system and imply that genetic variation in TIRAP may be linked to other IFN-γ-related diseases including autoimmunity and cancer.