Ma, Wing Tung; (2025) Interplay between cytokines and senescence in NK-like cytotoxicity in T cells. Doctoral thesis (Ph.D), UCL (University College London).

Preview

Text Ma_10206427_thesis.pdf Download (6MB) | Preview

Abstract

The accumulation of senescent cells is a hallmark of ageing and recent reports have correlated the age-related alteration of the immune system to the increased severity of immunopathology in older individuals. Due to the functional shift in senescent CD8+ T cells from antigen-specific T cell receptor (TCR)-mediated cytotoxic approach to a non-specific NK-like cytotoxic targeting, it was theorised that off-target tissue damage could occur more frequently with the increased senescent CD8+ T cells in the ageing population. To our knowledge, no study has been done to demonstrate whether the senescent CD8+ T cell subset can target primary autologous stromal cells and perform direct lysis via a TCR-independent manner. The goal of this project was to investigate the NK-like cytotoxic capability of senescent CD8+ T cells and its interplay with cytokine stimulations and immune regulation between primary autologous cells. Optimised cytotoxicity assays were used to quantify the NK-killing capabilities of CD8+ T cell subsets against cell lines and autologous stromal cells. IL-15 was predicted to be a crucial upstream regulator that induces differential cytotoxic pathways between naïve and senescent CD8+ T cells, and was later verified as the cytokine essential for activating NK-killing in the CD8+ and CD4+ T cells. Proteomic study revealed that IL-15 upregulated multiple pathways, including improved glycolysis and improved lytic granule trafficking, to allow senescent CD8+ T cells with inherently high cytotoxic potential and NKG2D machinery expressions to target K562 cells and perform NK-killing. Surprisingly, the same IL-15-induced NK-killing was unable to be triggered against primary fibroblasts, suggesting the immune interaction involving primary cells required a more complex balancing of activating and inhibitory signals generated by additional NK receptors than NKG2D alone. Using antigen-specific T cell clones and cytokine mixture recreating immunopathological lesions’ pro-inflammatory environment, it was found that the acquisition of NK-killing capability in T cells was not restricted by antigen-specificities, and additional SASP-related cytokines IL-1β, IL-6, IL-8 and IL-18 were essential for naïve CD8+ T cells and senescent CD4+ T cells to perform NK-killing on stimulated fibroblasts. Overall, this study highlighted the tightly regulated NK-killing capabilities in different T cell subsets were modified by distinct age-related cytokines, and proposed that the increase of these SASP cytokines during infections could promote non-specific tissue damage in older individuals. By providing direct quantification results of cytotoxicity mediated by NKG2D in different T cell subsets, we contributed to a deeper understanding that the novel NK-like functionalities in T cells may be intended for infection control rather than senescence control.

Download activity - last month

Export as JSONXMLCSV

Download activity - last 12 months

Export as JSONXMLCSV

Downloads by country - last 12 months

Export as JSONXMLCSV

Archive Staff Only

View Item