VISTA expression by microglia decreases during inflammation and is differentially regulated in CNS diseases

Abstract

V‐type immunoglobulin domain‐containing suppressor of T‐cell activation (VISTA) is a negative checkpoint regulator (NCR) involved in inhibition of T cell‐mediated immunity. Expression changes of other NCRs (PD‐1, PD‐L1/L2, CTLA‐4) during inflammation of the central nervous system (CNS) were previously demonstrated, but VISTA expression in the CNS has not yet been explored. Here, we report that in the human and mouse CNS, VISTA is most abundantly expressed by microglia, and to lower levels by endothelial cells. Upon TLR stimulation, VISTA expression was reduced in primary neonatal mouse and adult rhesus macaque microglia in vitro. In mice, microglial VISTA expression was reduced after lipopolysaccharide (LPS) injection, during experimental autoimmune encephalomyelitis (EAE), and in the accelerated aging Ercc1 Δ/− mouse model. After LPS injection, decreased VISTA expression in mouse microglia was accompanied by decreased acetylation of lysine residue 27 in histone 3 in both its promoter and enhancer region. ATAC‐sequencing indicated a potential regulation of VISTA expression by Pu.1 and Mafb, two transcription factors crucial for microglia function. Finally, our data suggested that VISTA expression was decreased in microglia in multiple sclerosis lesion tissue, whereas it was increased in Alzheimer's disease patients. This study is the first to demonstrate that in the CNS, VISTA is expressed by microglia, and that VISTA is differentially expressed in CNS pathologies.

VISTA: Coming of age as a multi-lineage immune checkpoint

“…While VISTA is not expressed on B cells, it is significantly expressed on plasma cells ( Lines and ElTanbouly, unpublished observations). Of note, we and others have detected reduced VISTA expression under inflammatory conditions .…”

“…As these TFs are up‐regulated under inflammatory conditions, we predict that they are potential repressors of VISTA expression. In line with this, deacetylation of H3K27 upstream of the Vsir gene in response to lipopolysaccharide (LPS) has also been reported, suggesting an additional layer of regulation upon inflammation that can reduce VISTA expression . The genomic locus containing Vsir is unique among other immunoregulatory molecules.…”

“…By viewing the Immgen database , we observed that both VISTA and PSGL‐1 have their highest expression on microglia. While the role of PSGL‐1 is not clearly established in microglia, VISTA plays a critical regulatory role as a checkpoint of microglia activation and restricts their proinflammatory polarization . Both VISTA and PSGL‐1 are also highly expressed on granulocytes, macrophages and endothelial cells and play important functions in their biology .…”

“…V‐set immunoglobulin domain suppressor of T cell activation (VISTA) is an immunoregulatory receptor expressed on most cell subsets of the hematopoietic lineage . Myeloid cells present the highest levels of VISTA expression, with a remarkably high level on microglia and neutrophils . This is followed by other myeloid subsets, including monocytes, macrophages, basophils and dendritic cells.…”

Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program

“…Vsir (or VISTA) is an immune checkpoint gene that inhibits T cell response (Xu et al, 2018) and is highly conserved in all microglia (Figures 3C and S3C). Its expression has been shown to be increased in several neurological diseases, such as AD (Borggrewe et al, 2018). Interestingly, previously identified markers for yolk-sac-derived microglia (e.g., Daglb,Bin1,Cst3,Sall1,Prpsap2,Entpd1,Tmem119,P2ry12,and CD81;Figures 3B,3C,and S3C) were present in core microglia clusters 1-3.…”