Exploring the VISTA of microglia: immune checkpoints in CNS inflammation
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REVIEW
Exploring the VISTA of microglia: immune checkpoints in CNS inflammation Malte Borggrewe 1
&
Susanne M. Kooistra 1 & Randolph J. Noelle 2 & Bart J. L. Eggen 1 & Jon D. Laman 1
Received: 24 June 2020 / Revised: 13 August 2020 / Accepted: 17 August 2020 # The Author(s) 2020
Abstract Negative checkpoint regulators (NCR) are intensely pursued as targets to modulate the immune response in cancer and autoimmunity. A large variety of NCR is expressed by central nervous system (CNS)-resident cell types and is associated with CNS homeostasis, interactions with peripheral immunity and CNS inflammation and disease. Immunotherapy blocking NCR affects the CNS as patients can develop neurological issues including encephalitis and multiple sclerosis (MS). How these treatments affect the CNS is incompletely understood, since expression and function of NCR in the CNS are only beginning to be unravelled. V-type immunoglobulin-like suppressor of T cell activation (VISTA) is an NCR that is expressed primarily in the haematopoietic system by myeloid and T cells. VISTA regulates T cell quiescence and activation and has a variety of functions in myeloid cells including efferocytosis, cytokine response and chemotaxis. In the CNS, VISTA is predominantly expressed by microglia and macrophages of the CNS. In this review, we summarize the role of NCR in the CNS during health and disease. We highlight expression of VISTA across cell types and CNS diseases and discuss the function of VISTA in microglia and during CNS ageing, inflammation and neurodegeneration. Understanding the role of VISTA and other NCR in the CNS is important considering the adverse effects of immunotherapy on the CNS, and in view of their therapeutic potential in CNS disease. Keywords Neurodegeneration . Neuroinflammation . Glia cells . Brain disease . Homeostasis
Introduction Immune checkpoints are critical in maintaining the balance between protective immune responses of appropriate magnitude versus excessive inflammation with undue tissue damage and autoimmune disease. Co-stimulatory and co-inhibitory receptors provide T cells with activating or suppressing signals, respectively, and a disruption of this balance can lead to autoimmunity or prevent specific immune responses. Negative checkpoint regulators (NCR) are receptors that provide co-inhibitory signals to T cells, which lead to inhibition of T cell activation. Targeting immune checkpoints and
* Jon D. Laman [email protected] 1
Department of Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
2
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, NH, USA
particularly NCR are intensely pursued as therapeutic targets for cancer and autoimmunity. Blocking NCR enhances antitumour immunity, whereas enhancing NCR signalling offers a strategy to alleviate autoimmunity. Studies mainly focus on NCR biology in cancer and peripheral im
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