Lötscher, Jonas. Shaping memory with magnesium – how moderate activation of LFA-1 with magnesium optimizes CD8+ T cell effector function. 2020, Doctoral Thesis, University of Basel, Faculty of Science.
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Abstract
While intracellular magnesium (Mg2+) plays established and important roles in key cellular processes, the biologic relevance of extracellular Mg2+ remains largely unknown.
Here we show that in Mg2+-rich environments CD8+ T cell mediated cancer- and infection control were both improved. Surprisingly therefore, extracellular Mg2+ was distinctly compartmentalized across anatomic sites, creating naturally Mg2+ deplete tissues. Moderate activation of LFA-1 was underpinning Mg2+-mediated improvement of CD8+ T cell functionality by supporting: Ca2+ flux; signal transduction; cell activation; metabolic reprogramming; immune synapse formation and specific cytotoxic activity. Blocking LFA-1, excessive LFA-1 stabilization, as well as overriding LFA-1 signaling all hindered optimal CD8+ T cell function. This principle translated to the performance of CAR T cells, in vitro and in vivo, and low serum Mg2+ levels were associated with more rapid disease progression and poor survival in CAR T cell treated patients.
Mg2+ thus operates as a site-specific modulator of CD8+ T cell immunity. Specifically, moderate stabilization of LFA-1 with Mg2+ was hitting an unrecognized sweet spot optimizing CD8+ T cell effector function. This insight has important implications for efforts to harness the Mg2+–LFA-1 axis for immunotherapy
Here we show that in Mg2+-rich environments CD8+ T cell mediated cancer- and infection control were both improved. Surprisingly therefore, extracellular Mg2+ was distinctly compartmentalized across anatomic sites, creating naturally Mg2+ deplete tissues. Moderate activation of LFA-1 was underpinning Mg2+-mediated improvement of CD8+ T cell functionality by supporting: Ca2+ flux; signal transduction; cell activation; metabolic reprogramming; immune synapse formation and specific cytotoxic activity. Blocking LFA-1, excessive LFA-1 stabilization, as well as overriding LFA-1 signaling all hindered optimal CD8+ T cell function. This principle translated to the performance of CAR T cells, in vitro and in vivo, and low serum Mg2+ levels were associated with more rapid disease progression and poor survival in CAR T cell treated patients.
Mg2+ thus operates as a site-specific modulator of CD8+ T cell immunity. Specifically, moderate stabilization of LFA-1 with Mg2+ was hitting an unrecognized sweet spot optimizing CD8+ T cell effector function. This insight has important implications for efforts to harness the Mg2+–LFA-1 axis for immunotherapy
Advisors: | Hess, Christoph and Handschin, Christoph and Ho, Ping-Chih |
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Faculties and Departments: | 03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Allgemeine innere Medizin USB > Ambulante innere Medizin (Hess C) 03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Allgemeine innere Medizin USB > Ambulante innere Medizin (Hess C) 03 Faculty of Medicine > Departement Biomedizin > Associated Research Groups > Pharmakologie (Handschin) |
UniBasel Contributors: | Lötscher, Jonas and Hess, Christoph and Handschin, Christoph |
Item Type: | Thesis |
Thesis Subtype: | Doctoral Thesis |
Thesis no: | 14874 |
Thesis status: | Complete |
Number of Pages: | 72 |
Language: | English |
Identification Number: |
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edoc DOI: | |
Last Modified: | 06 Dec 2022 05:30 |
Deposited On: | 05 Dec 2022 09:55 |
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