Biology subjects

Callender, L. A.

Publications and source records attributed to Callender, L. A..

3 recordsLinked to original sources

bioRxiv2025

Characterisation of the dual roles of senescent-like T cells that arise during healthy and unhealthy ageing

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 TEMRA 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 TEMRA cells, which can preserve cytotoxic function through acquisition of NK-cell receptors, T2D-associated TEMRA cells showed reduced surface expression of KLRG1, NKG2D and NKG2A together with defective receptor recycling. TGF{beta}1 was elevated in T2D and reproduced several features of this phenotype in vitro, including increased TEMRA 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 TEMRA cells with diminished effector capacity may compromise immune function. Together, these findings identify a distinct senescent-like CD8 TEMRA state linking metabolic inflammation to dysregulated T cell differentiation.

immunology↗

bioRxiv2019

GATA3 controls mitochondrial biogenesis in primary human CD4+ T cells during DNA damage

Introductory paragraphGATA binding protein 3 (GATA3) has traditionally been regarded as a lineage-specific transcription factor that drives the differentiation of CD4+ T helper (Th) 2 cells. However, increasing evidence shows that GATA3 is involved in a myriad of processes such as immune regulation, proliferation and maintenance in other T cell and non-T cell lineages. We show here a previously unknown mechanism utilized by CD4+ T cells to increase mitochondrial mass in response to DNA damage through the binding of GATA3, AMP-activated protein kinase (AMPK), peroxisome-proliferator-activated receptor {gamma} co-activator-1 (PGC1), nuclear factor erythroid 2-related factor 2 (NRF2) and superoxide dismutase 3 (SOD3) to the DNA damage repair (DDR) component ATR. These findings extend the pleotropic nature of GATA3 and highlight the potential for GATA3-targeted cell manipulation for clinical interventions.

immunology↗

bioRxiv2019

Mitochondrial mass governs the extent of T cell senescence

The susceptibility of human CD4+ and CD8+ T cells to senesce differs, with CD8+ T cells acquiring an immunosenescent phenotype faster than their 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. Mitochondrial dysfunction has been linked to both cellular senescence and ageing, however it is still unclear whether mitochondria play a causal role in senescence. Our data shows 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.

immunology↗