Magnesium sensing via LFA-1 regulates CD8 + T cell effector function

Cell. 2022 Feb 17;185(4):585-602.e29. doi: 10.1016/j.cell.2021.12.039. Epub 2022 Jan 19.

Abstract

The relevance of extracellular magnesium in cellular immunity remains largely unknown. Here, we show that the co-stimulatory cell-surface molecule LFA-1 requires magnesium to adopt its active conformation on CD8+ T cells, thereby augmenting calcium flux, signal transduction, metabolic reprogramming, immune synapse formation, and, as a consequence, specific cytotoxicity. Accordingly, magnesium-sufficiency sensed via LFA-1 translated to the superior performance of pathogen- and tumor-specific T cells, enhanced effectiveness of bi-specific T cell engaging antibodies, and improved CAR T cell function. Clinically, low serum magnesium levels were associated with more rapid disease progression and shorter overall survival in CAR T cell and immune checkpoint antibody-treated patients. LFA-1 thus directly incorporates information on the composition of the microenvironment as a determinant of outside-in signaling activity. These findings conceptually link co-stimulation and nutrient sensing and point to the magnesium-LFA-1 axis as a therapeutically amenable biologic system.

Keywords: CAR T cells; Mg2+; T cell engaging antibodies; co-stimulation/LFA-1; immune control; integration of microenvironment and T cell function; magnesium; memory CD8 T cells; microenvironment; tumor-specific T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Infections / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • Caloric Restriction
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic
  • HEK293 Cells
  • Humans
  • Immunologic Memory
  • Immunological Synapses / metabolism
  • Immunotherapy
  • Lymphocyte Activation / immunology
  • Lymphocyte Function-Associated Antigen-1 / metabolism*
  • MAP Kinase Signaling System
  • Magnesium / administration & dosage
  • Magnesium / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Neoplasms / therapy
  • Phenotype
  • Phosphorylation
  • Proto-Oncogene Proteins c-jun / metabolism

Substances

  • Lymphocyte Function-Associated Antigen-1
  • Proto-Oncogene Proteins c-jun
  • Magnesium