Shaping memory with magnesium – how moderate activation of LFA-1 with magnesium optimizes CD8+ T cell effector function

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