SerpinB1 controls encephalitogenic T helper cells in neuroinflammation

Abstract

SerpinB1, a protease inhibitor and neutrophil survival factor, was recently linked with IL-17–expressing T cells. Here, we show that serpinB1 (Sb1) is dramatically induced in a subset of effector CD4 cells in experimental autoimmune encephalomyelitis (EAE). Despite normal T cell priming, Sb1−/− mice are resistant to EAE with a paucity of T helper (TH) cells that produce two or more of the cytokines, IFNγ, GM-CSF, and IL-17. These multiple cytokine-producing CD4 cells proliferate extremely rapidly; highly express the cytolytic granule proteins perforin-A, granzyme C (GzmC), and GzmA and surface receptors IL-23R, IL-7Rα, and IL-1R1; and can be identified by the surface marker CXCR6. In Sb1−/− mice, CXCR6+ TH cells are generated but fail to expand due to enhanced granule protease-mediated mitochondrial damage leading to suicidal cell death. Finally, anti-CXCR6 antibody treatment, like Sb1 deletion, dramatically reverts EAE, strongly indicating that the CXCR6+ T cells are the drivers of encephalitis.

CXCR6 is required for antitumor efficacy of intratumoral CD8+T cell

“…These results indicate that CXCR6 still identifies highly activated and cytolytic T cell subset, consistent with its role in autoimmune diseases. 16 Immune checkpoint therapy targeting the CTLA-4 or PD-1/PD-L1 pathways can induce inflammatory toxicities such as checkpoint inhibitor-induced colitis. 26 27 Singlecell sequencing data reported recently that a striking accumulation of CD8 + T cells with highly cytotoxic and proliferative states is observed in checkpoint inhibitorinduced colitis, which is highly expressed CXCR6.…”

“…Given that T cells in autoimmune diseases are often highly activated and inflammatory, while exhausted or repressed in tumor, we question that whether the same phenotypic T cells are still immunocompetent in tumors according to the phenotypic characteristics of highly activated inflammatory T cells in autoimmune diseases. In MS and mouse EAE models, CXCR6 identifies a group of pathogenic cells with excessive immune function, 16 so this study focused on the expression of CXCR6 in the tumor microenvironment and the relationship between CXCR6 expression and CD8 + T cell function. We started with single-cell sequencing data of clinical clone cancer samples 17 and combined transcriptome sequencing in the TCGA database and experimental results to validate CXCR6 was almost exclusively expressed in tumor tissues and highly expressed on CD8 + T cells ( figure 1 ).…”

“…These results indicate that CXCR6 still identifies highly activated and cytolytic T cell subset, consistent with its role in autoimmune diseases. 16 …”

“…For example, whether CXCR6 is related to the prognosis of cancer patients, how environmental factors regulate CXCR6 positive cells and more research is needed to confirm the role of CXCR6 in tumor development. Interestingly, Hou et al 16 reveals that in multiple sclerosis (MS) and mouse experimental encephalomyelitis (EAE) models, CXCR6 identifies a subcluster of T cells with inflammatory cytokine secretion, a cytolytic system, and extremely rapid proliferation. Therefore, we wonder whether there still exist the same phenotypic immunocompetent T cells in tumors according to the phenotypic characteristics of highly activated inflammatory T cells in autoimmune diseases.…”

Assessing the Role of Long Noncoding RNA in Nucleus Accumbens in Subjects With Alcohol Dependence

“…A,B). SERPINB1 has been linked to neuroinflammation (Hou et al, 2019), whereas S100A11 exhibits one of the most significant coexpression differences between schizophrenia and bipolar disorder (Baumont et al, 2015). Nevertheless, our results demonstrate that the complex interactions between the coding and noncoding transcriptome observed in the neuropathology of AD are, at least partially, modulated by the genetic factors (Mamdani et al, 2015; Sartor et al, 2012).…”