<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Development and homeostasis of memory CD8+ T cells and\r\nimplications for cancer immunotherapy"^^ . "The defining feature of the adaptive immune system is the development of long-lived memory\r\ncells that are able to respond more vigorously upon recurrent pathogen encounters. Based\r\non their recirculation potential, memory CD8+ T cells are categorised into central memory T\r\n(TCM), effector memory T (TEM), and resident memory T (TRM) cells. Compared to effector\r\nCD8+ T cells, TCM cells are more adept at controlling tumour growth when used for adoptive\r\nT cell therapy (ACT). However, transferred memory cells eventually develop functional exhaustion, and durable responses to ACT are observed in, at best, 50% of patients with solid malignancies.\r\nHere, I show that elevated CD8 levels in TCM cells could be harnessed to improve the antitumour function of adoptively transferred, memory-like CD8+ T cells in a mouse melanoma\r\nmodel. CD8α ligation with an agonistic antibody activated proximal TCR signalling and induced a hybrid effector/memory differentiation state. CD8-ligated cells displayed enhanced\r\nproliferation, cytotoxicity, and glycolysis without compromising memory cell-like persistence and oxidative phosphorylation. Effector cytokine production in CD8-ligated cells was\r\ndependent on rewired glucose and glutamine metabolism. Expansion of memory-like CD8+\r\nT cells in presence of this agonistic antibody significantly enhanced their tumoricidal function in vivo. Furthermore, agonistic CD8 Fab′ partially rescued T cell dysfunction, induced\r\nthe proliferation of progenitor exhausted T cells, and significantly reduced tumour burden.\r\nThese findings establish CD8 as an immunotherapeutic target that does not require prior\r\nknowledge of the patients’ TCR repertoire.\r\nInterleukin (IL) 15 is required for survival and homeostatic turnover of all memory CD8+\r\nT cell subsets, but its cellular source remains undefined. Using a mouse model of acute infection with lymphocytic choriomeningitis virus (LCMV), I demonstrate that in spite of IL-15 being widely expressed, different memory T cell subsets rely on distinct IL-15 sources for maintenance. Terminal TEM (tTEM) cells in particular are significantly depleted in mice with CD4+\r\nregulatory T (Treg) cell-specific Il15 deletion. These results show that Treg cells play a direct\r\nrole in supporting the diversity of the memory immune response.\r\nFinally, I provide preliminary evidence that signal transducer and activator of transcription (Stat) 6 activation downstream of IL-4 signalling controls the infiltration of circulating\r\nT cells into non-lymphoid tissues and their subsequent development into TRM cells. Using\r\nmouse models of infection with LCMV and influenza, I show that CD8+ T cell-intrinsic Stat6\r\nsignalling induces the migration of T cells into liver and lung, respectively, possibly by modulating the expression of the chemokine receptor C-X-C Motif Chemokine Receptor 6 (CXCR6).\r\nTogether, the data presented here explore different aspects of all memory T cell subsets\r\nand provide insights into the development of TRM cells, the homeostatic requirements of\r\nTEM cells, and the transferability of TCM biology to the field of tumour immunotherapy."^^ . "2024" . . . . . . . "Alaa Abdelghani Mohamed"^^ . "Madi"^^ . "Alaa Abdelghani Mohamed Madi"^^ . . . . . . "Development and homeostasis of memory CD8+ T cells and\r\nimplications for cancer immunotherapy (PDF)"^^ . . . "thesis.pdf"^^ . . . "Development and homeostasis of memory CD8+ T cells and\r\nimplications for cancer immunotherapy (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Development and homeostasis of memory CD8+ T cells and\r\nimplications for cancer immunotherapy (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Development and homeostasis of memory CD8+ T cells and\r\nimplications for cancer immunotherapy (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Development and homeostasis of memory CD8+ T cells and\r\nimplications for cancer immunotherapy (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Development and homeostasis of memory CD8+ T cells and\r\nimplications for cancer immunotherapy (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #32848 \n\nDevelopment and homeostasis of memory CD8+ T cells and \nimplications for cancer immunotherapy\n\n" . "text/html" . .