CXCR6: Targeting a rogue T cell prevents and reverses multiple sclerosis in mice

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CXCR6: Targeting a rogue T cell prevents and reverses multiple sclerosis in mice

Post by NHE » Sat Oct 05, 2019 4:07 pm

Targeting a rogue T cell prevents and reverses multiple sclerosis in mice
https://medicalxpress.com/news/2019-10- ... rosis.html
MedicalExpress wrote:Multiple sclerosis is an autoimmune disease affecting both adults and children. It's driven by "helper" T cells, white blood cells that mount an inflammatory attack on the brain and spinal cord, degrading the protective myelin sheath that covers nerve fibers. But there are many different kinds of T helper cells, and up until now, no one knew which ones were the bad actors.

Researchers at Boston Children's Hospital have now pinpointed the specific helper T cells that cause MS, as well as a protein on their surface that marks them. As reported this week in PNAS, an antibody targeting this protein, CXCR6, both prevented and reversed MS in a mouse model.

If human studies bear out the findings, targeting these rogue T cells could potentially ameliorate MS, says senior investigator Eileen Remold-O'Donnell, PhD, of the hospital's Program in Cellular and Molecular Medicine. She believes the findings could also apply to other forms of autoimmune encephalomyelitis (inflammation of the brain and spinal cord), as well as inflammatory arthritis.

"We've demonstrated in mice you can target these cells and get rid of them," she says. "We don't know if this approach would be appropriate for all cases of MS, but it could be effective in the early inflammatory stages of the disease, and in targeting newly formed cells during disease exacerbations."

Profiling MS-inducing cells

Recent efforts to pinpoint the T helper cells causing MS have pointed to TH17 cells, but some TH17 cells appear not to be involved. Remold-O'Donnell and her former postdoctoral fellow Lifei Hou, PhD, zeroed in on a subset of fast-proliferating TH17-derived cells, all bearing the CXCR6 marker. These cells, they showed, are highly damaging to nerve fibers, producing one set of proteins that directly damage cells and others, including GM-CSF, that stimulate an inflammatory attack by other immune cells known as macrophages.

The CXCR6-positive cells also produce increased amounts of a protein called SerpinB1 (Sb1), the researchers showed. When they deleted the Sb1 gene in T cells in their mouse model, fewer immune cells survived to infiltrate the spinal cord. The mice also displayed fewer symptoms of disease than control mice. Moreover, these Sb1-containing cells could be readily identified with antibodies targeting the CXCR6 surface protein.

Human counterparts

But are CXCR6+ cells relevant in human disease? To investigate, Remold-O'Donnell and Hou worked with rheumatologists, immunologists, and neuro-immunologists at Boston Children's and Brigham and Women's Hospital.

They obtained and tested samples of blood and synovial fluid (from the cavities of joints) from patients with inflammatory autoimmune arthritis. Levels of CXCR6+ cells were indeed elevated in the inflamed joints, but not in circulating blood from the arthritis patients, patients with MS, or healthy controls.

Targeting CXCR6 in multiple sclerosis

Remold-O'Donnell and Hou, first author on the paper, believe treatments to deplete CXCR6+ cells could mitigate MS and possibly other autoimmune disorders while largely leaving other T cell immune defenses intact. When they used monoclonal antibodies to target CXCR6, the harmful cells largely disappeared, and mice, which were primed to get MS, did not develop the disease.

The two have filed a patent covering the work and have formed a company, Edelweiss Immune, Inc., in which they have equity ownership together with Boston Children's Hospital. The new company will be carrying the research forward.

"Many drugs have been developed to treat autoimmune diseases, such as glucocorticoids and cytotoxic reagents," says Hou. "However, none selectively target pathogenic T cells, and long-term use of immunosuppressive agents results in broad immunosuppression and compromised immune defenses. Therapeutics with better selectivity, safety, and efficacy are needed."

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Re: CXCR6: Targeting a rogue T cell prevents and reverses multiple sclerosis in mice

Post by NHE » Sat Oct 05, 2019 4:17 pm

SerpinB1 controls encephalitogenic T helper cells in neuroinflammation
https://www.pnas.org/content/early/2019 ... 1905762116
  • Significance: The study addresses a basic immunology topic with considerable clinical relevance, namely the nature of the pathogenic T helper cells that drive autoimmune disorders like multiple sclerosis (MS) and inflammatory arthritis. Using mouse MS, we identify precursors of the encephalitogenic/pathogenic T cells based on their dependence on the protease inhibitor SerpinB1. Newly identified signature genes reveal the unusual nature of these T cells that combine (i) inflammatory cytokine secretion, (ii) a cytolytic system, and (iii) extreme rapid proliferation. We demonstrate that their survival/expansion depends on SerpinB1 and involves regulation of a proliferation-associated protease-mediated cell suicide mechanism. Importantly, we discovered that cell surface CXCR6 is an exquisite marker of pathogenic T helper cells and demonstrated that anti-CXCR6 treatment has potential to prevent or mitigate MS.

    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.

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Re: CXCR6: Targeting a rogue T cell prevents and reverses multiple sclerosis in mice

Post by NHE » Thu Oct 17, 2019 8:21 am

Smoking increases CXCR6 expression. This may be a potential link explaining why smoking accelerates MS progression.

Cigarette Smoke Increases Endothelial CXCL16-Leukocyte CXCR6 Adhesion In Vitro and In Vivo. Potential Consequences in Chronic Obstructive Pulmonary Disease
Front Immunol. 2017 Dec 13;8:1766.
  • Cardiovascular disease (CVD) is a major comorbidity in chronic obstructive pulmonary disease (COPD). Although the mechanism of its development remains largely unknown, it appears to be associated with cigarette consumption and reduced lung function. Therefore, the aim of this study was to investigate the potential link between water-soluble cigarette smoke extract (CSE)-induced endothelial dysfunction and the function of CXCL16/CXCR6 axis on the initial attachment of leukocytes, in addition to its possible impact on COPD-associated systemic inflammation. To do this, we employed several experimental approaches, including RNA silencing and flow cytometry analysis, the dynamic flow chamber technique, and intravital microscopy in the cremasteric arterioles of animals exposed to cigarette smoke (CS). CSE-induced arterial CXCL16 expression, leading to increased platelet-leukocyte and mononuclear cell adhesiveness. CSE-induced CXCL16 expression was dependent on Nox5 expression and subsequent RhoA/p38 MAPK/NF-κB activation. Flow cytometry analysis revealed that COPD patients (n = 35) presented greater numbers of activated circulating platelets (PAC-1+ and P-selectin+) expressing CXCL16 and CXCR6 as compared with age-matched controls (n = 17), with a higher number of CXCR6+-platelets in the smoking COPD group than in ex-smokers. This correlated with enhanced circulating CXCR6+-platelet-leukocyte aggregates in COPD patients. The increase in circulating numbers of CXCR6-expressing platelets and mononuclear cells resulted in enhanced platelet-leukocyte and leukocyte adhesiveness to CSE-stimulated arterial endothelium, which was greater than that found in age-matched controls and was partly dependent on endothelial CXCL16 upregulation. Furthermore, CS exposure provoked CXCL16-dependent leukocyte-arteriolar adhesion in cremasteric arterioles, which was significantly reduced in animals with a nonfunctional CXCR6 receptor. In conclusion, we provide the first evidence that increased numbers of CXCR6-expressing circulating platelets and mononuclear leukocytes from patients with COPD might be a marker of systemic inflammation with potential consequences in CVD development. Accordingly, CXCL16/CXCR6 axis blockade might constitute a new therapeutic approach for decreasing the risk of CVD in COPD patients.
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Re: CXCR6: Targeting a rogue T cell prevents and reverses multiple sclerosis in mice

Post by NHE » Thu Oct 17, 2019 10:22 am

CXCR6+ T cells are active in other autoimmune diseases such as rheumatoid arthritis.

Elevated CXCL16 expression by synovial macrophages recruits memory T cells into rheumatoid joints.
Arthritis Rheum. 2005 May;52(5):1381-91.
  • OBJECTIVE: Directional migration of leukocytes is orchestrated by the regulated expression of chemokine receptors and their ligands. The receptor CXCR6 is abundantly expressed by Th1-polarized effector/memory lymphocytes accumulating at inflammatory sites. This study was undertaken to examine the presence of CXCR6+ T cells and of CXCL16, the only ligand for CXCR6, in the joints of patients with rheumatoid arthritis (RA).

    METHODS: Flow cytometry analysis of the expression of CXCR6 by peripheral blood and synovial fluid (SF) T cells. In addition, by performing conventional and real-time reverse transcriptase-polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay, we determined the expression of CXCL16 and its protease ADAM-10 within synovium and by cultured macrophages. SF T cell migration was studied with the Transwell system.

    RESULTS: Accumulation of CXCR6+ T cells within RA SF coincided with highly elevated levels of CXCL16+ macrophages. In vitro studies revealed that monocytes started to express CXCL16 upon differentiation into macrophages, and that RA SF and tumor necrosis factor (TNF) enhanced CXCL16 expression. Moreover, RA patients responding to anti-TNF therapy showed a strongly decreased CXCL16 expression, whereas nonresponding patients did not. Interestingly, ADAM-10, a recently identified protease of CXCL16, was abundantly expressed by CXCL16+ macrophages in vitro and in RA in vivo, which resulted in increased levels of cleaved CXCL16 in RA SF relative to controls. Finally, CXCR6+ T cells from RA SF were attracted by CXCL16.

    CONCLUSION: These data provide evidence that enhanced production of CXCL16 in RA synovia leads to recruitment of CXCR6+ memory T cells, thereby contributing to the inflammatory cascade associated with RA pathology.
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