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

Jonas Lötscher; Adrià Arnau Martí i Líndez; Nicole Kirchhammer; Elisabetta Cribioli; Greta Maria Paola Giordano Attianese; Marcel P. Trefny; Markus Lenz; Sacha I. Rothschild; Paolo Strati; Marco Künzli; Claudia Lotter; Susanne H. Schenk; Philippe Dehio; Jordan Löliger; Ludivine Litzler; David Schreiner; Victoria Koch; Nicolas Page; Dahye Lee; Jasmin Grählert; Dmitry Kuzmin; Anne Valérie Burgener; Doron Merkler; Miklos Pless; Maria L. Balmer; Walter Reith; Jörg Huwyler; Melita Irving; Carolyn G. King; Alfred Zippelius; Christoph Hess

doi:10.1016/j.cell.2021.12.039

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

Jonas Lötscher, Adrià Arnau Martí i Líndez, Nicole Kirchhammer, Elisabetta Cribioli, Greta Maria Paola Giordano Attianese, Marcel P. Trefny, Markus Lenz, Sacha I. Rothschild, Paolo Strati, Marco Künzli, Claudia Lotter, Susanne H. Schenk, Philippe Dehio, Jordan Löliger, Ludivine Litzler, David Schreiner, Victoria Koch, Nicolas Page, Dahye Lee, Jasmin GrählertDmitry Kuzmin, Anne Valérie Burgener, Doron Merkler, Miklos Pless, Maria L. Balmer, Walter Reith, Jörg Huwyler, Melita Irving, Carolyn G. King, Alfred Zippelius, Christoph Hess

Lymphoma-Myeloma

Research output: Contribution to journal › Article › peer-review

82 Scopus citations

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.

Original language	English (US)
Pages (from-to)	585-602.e29
Journal	Cell
Volume	185
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2021.12.039
State	Published - Feb 17 2022

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.cell.2021.12.039

Cite this

Lötscher, J., Martí i Líndez, A. A., Kirchhammer, N., Cribioli, E., Giordano Attianese, G. M. P., Trefny, M. P., Lenz, M., Rothschild, S. I., Strati, P., Künzli, M., Lotter, C., Schenk, S. H., Dehio, P., Löliger, J., Litzler, L., Schreiner, D., Koch, V., Page, N., Lee, D., ... Hess, C. (2022). Magnesium sensing via LFA-1 regulates CD8⁺ T cell effector function. Cell, 185(4), 585-602.e29. https://doi.org/10.1016/j.cell.2021.12.039

Lötscher, J, Martí i Líndez, AA, Kirchhammer, N, Cribioli, E, Giordano Attianese, GMP, Trefny, MP, Lenz, M, Rothschild, SI, Strati, P, Künzli, M, Lotter, C, Schenk, SH, Dehio, P, Löliger, J, Litzler, L, Schreiner, D, Koch, V, Page, N, Lee, D, Grählert, J, Kuzmin, D, Burgener, AV, Merkler, D, Pless, M, Balmer, ML, Reith, W, Huwyler, J, Irving, M, King, CG, Zippelius, A & Hess, C 2022, 'Magnesium sensing via LFA-1 regulates CD8⁺ T cell effector function', Cell, vol. 185, no. 4, pp. 585-602.e29. https://doi.org/10.1016/j.cell.2021.12.039

@article{e70feef7d69d4962915fcb082a152bf5,

title = "Magnesium sensing via LFA-1 regulates CD8+ T cell effector function",

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, co-stimulation/LFA-1, immune control, integration of microenvironment and T cell function, magnesium, memory CD8 T cells, Mg2+, microenvironment, T cell engaging antibodies, tumor-specific T cells",

author = "Jonas L{\"o}tscher and {Mart{\'i} i L{\'i}ndez}, {Adri{\`a} Arnau} and Nicole Kirchhammer and Elisabetta Cribioli and {Giordano Attianese}, {Greta Maria Paola} and Trefny, {Marcel P.} and Markus Lenz and Rothschild, {Sacha I.} and Paolo Strati and Marco K{\"u}nzli and Claudia Lotter and Schenk, {Susanne H.} and Philippe Dehio and Jordan L{\"o}liger and Ludivine Litzler and David Schreiner and Victoria Koch and Nicolas Page and Dahye Lee and Jasmin Gr{\"a}hlert and Dmitry Kuzmin and Burgener, {Anne Val{\'e}rie} and Doron Merkler and Miklos Pless and Balmer, {Maria L.} and Walter Reith and J{\"o}rg Huwyler and Melita Irving and King, {Carolyn G.} and Alfred Zippelius and Christoph Hess",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2022",

month = feb,

day = "17",

doi = "10.1016/j.cell.2021.12.039",

language = "English (US)",

volume = "185",

pages = "585--602.e29",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "4",

}

TY - JOUR

T1 - Magnesium sensing via LFA-1 regulates CD8+ T cell effector function

AU - Lötscher, Jonas

AU - Martí i Líndez, Adrià Arnau

AU - Kirchhammer, Nicole

AU - Cribioli, Elisabetta

AU - Giordano Attianese, Greta Maria Paola

AU - Trefny, Marcel P.

AU - Lenz, Markus

AU - Rothschild, Sacha I.

AU - Strati, Paolo

AU - Künzli, Marco

AU - Lotter, Claudia

AU - Schenk, Susanne H.

AU - Dehio, Philippe

AU - Löliger, Jordan

AU - Litzler, Ludivine

AU - Schreiner, David

AU - Koch, Victoria

AU - Page, Nicolas

AU - Lee, Dahye

AU - Grählert, Jasmin

AU - Kuzmin, Dmitry

AU - Burgener, Anne Valérie

AU - Merkler, Doron

AU - Pless, Miklos

AU - Balmer, Maria L.

AU - Reith, Walter

AU - Huwyler, Jörg

AU - Irving, Melita

AU - King, Carolyn G.

AU - Zippelius, Alfred

AU - Hess, Christoph

PY - 2022/2/17

Y1 - 2022/2/17

N2 - 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.

AB - 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.

KW - CAR T cells

KW - co-stimulation/LFA-1

KW - immune control

KW - integration of microenvironment and T cell function

KW - magnesium

KW - memory CD8 T cells

KW - Mg2+

KW - microenvironment

KW - T cell engaging antibodies

KW - tumor-specific T cells

UR - http://www.scopus.com/inward/record.url?scp=85124572892&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85124572892&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.12.039

DO - 10.1016/j.cell.2021.12.039

M3 - Article

C2 - 35051368

AN - SCOPUS:85124572892

SN - 0092-8674

VL - 185

SP - 585-602.e29

JO - Cell

JF - Cell

IS - 4

ER -