PD-L1 positive astrocytes attenuate inflammatory functions of PD-1 positive microglia in models of autoimmune neuroinflammation

Mathias Linnerbauer, Tobias Beyer, Lucy Nirschl, Daniel Farrenkopf, Lena Lößlein, Oliver Vandrey, Anne Peter, Thanos Tsaktanis, Hania Kebir, David Laplaud, Rupert Oellinger, Thomas Engleitner, Jorge Ivan Alvarez, Roland Rad, Thomas Korn, Bernhard Hemmer, Francisco J. Quintana and Veit Rothhammer ()
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Mathias Linnerbauer: Friedrich-Alexander University Erlangen Nuremberg
Tobias Beyer: Technical University of Munich
Lucy Nirschl: Technical University of Munich
Daniel Farrenkopf: Friedrich-Alexander University Erlangen Nuremberg
Lena Lößlein: Friedrich-Alexander University Erlangen Nuremberg
Oliver Vandrey: Friedrich-Alexander University Erlangen Nuremberg
Anne Peter: Friedrich-Alexander University Erlangen Nuremberg
Thanos Tsaktanis: Friedrich-Alexander University Erlangen Nuremberg
Hania Kebir: University of Pennsylvania
David Laplaud: Center for Research in Transplantation et Translational Immunology, UMR 1064
Rupert Oellinger: Technical University of Munich
Thomas Engleitner: Technical University of Munich
Jorge Ivan Alvarez: University of Pennsylvania
Roland Rad: Technical University of Munich
Thomas Korn: Technical University of Munich
Bernhard Hemmer: Technical University of Munich
Francisco J. Quintana: Harvard Medical School
Veit Rothhammer: Friedrich-Alexander University Erlangen Nuremberg

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disorder of the central nervous system (CNS). Current therapies mainly target inflammatory processes during acute stages, but effective treatments for progressive MS are limited. In this context, astrocytes have gained increasing attention as they have the capacity to drive, but also suppress tissue-degeneration. Here we show that astrocytes upregulate the immunomodulatory checkpoint molecule PD-L1 during acute autoimmune CNS inflammation in response to aryl hydrocarbon receptor and interferon signaling. Using CRISPR-Cas9 genetic perturbation in combination with small-molecule and antibody-mediated inhibition of PD-L1 and PD-1 both in vivo and in vitro, we demonstrate that astrocytic PD-L1 and its interaction with microglial PD-1 is required for the attenuation of autoimmune CNS inflammation in acute and progressive stages in a mouse model of MS. Our findings suggest the glial PD-L1/PD-1 axis as a potential therapeutic target for both acute and progressive MS stages.

Date: 2023
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DOI: 10.1038/s41467-023-40982-8

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