Another TLO in the Wall: Education and Control of T Cells in Atherosclerotic Arteries

Onder, Lucas; Ludewig, Burkhard

doi:10.1016/j.immuni.2015.05.022

Cited by 2 publications

(2 citation statements)

References 13 publications

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“…Subsequent work placing vascular DCs at the media-adventitia border spatially separated the immunological injury and the tissue-destructive granuloma formation (58)(59)(60). In contrast to atherosclerotic disease, where the adventitia is attracting attention because it is the site of tertiary lymphoid organs (TLOs) (61)(62)(63), GCA-affected arteries do not form organized lymphoid architectures in the adventitia. In an elegant work, Hu et al (62) have implicated localized TLOs in regulating the immune responses promoting atherosclerotic lesions in the murine aorta, affecting T cell recruitment, T cell priming, and induction of regulatory T cells.…”

Section: Discussionmentioning

confidence: 99%

The microvascular niche instructs T cells in large vessel vasculitis via the VEGF-Jagged1-Notch pathway

et al. 2017

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Microvascular networks in the adventitia of large arteries control access of inflammatory cells to the inner wall layers (media and intima) and thus protect the immune privilege of the aorta and its major branches. In the autoimmune vasculitis giant cell arteritis (GCA), CD4 T helper 1 (TH1) and TH17 cells invade into the wall of the aorta and large elastic arteries to form tissue-destructive granulomas. Whether the disease microenvironment provides instructive cues for vasculitogenic T cells is unknown. We report that adventitial microvascular endothelial cells (mvECs) perform immunoregulatory functions by up-regulating expression of the Notch ligand Jagged1. Vascular endothelial growth factor (VEGF), abundantly present in GCA patients’ blood, induced Jagged1 expression, allowing mvECs to regulate effector T cell induction via the Notch-mTORC1 (mammalian target of rapamycin complex 1) pathway. We found that circulating CD4 T cells in GCA patients have left the quiescent state, actively signal through the Notch pathway and differentiate into TH1 and TH17 effector cells. In an in vivo model of large vessel vasculitis, exogenous VEGF functioned as an effective amplifier to recruit and activate vasculitogenic T cells. Thus, systemic VEGF co-opts endothelial Jagged1 to trigger aberrant Notch signaling, biases responsiveness of CD4 T cells, and induces pathogenic effector functions. Adventitial microvascular networks function as an instructive tissue niche, which can be exploited to target vasculitogenic immunity in large vessel vasculitis.

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Section: Discussionmentioning

confidence: 99%

The microvascular niche instructs T cells in large vessel vasculitis via the VEGF-Jagged1-Notch pathway

et al. 2017

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“…Several studies have shown that TLO support protective immunity against a variety of pathogens (46, 47, 58) or cause tissue damage in inflammatory and autoimmune diseases (15, 69–72). Interestingly, presence of TLO in solid tumors correlated with a favorable clinical outcome (18, 19).…”

Section: Discussionmentioning

confidence: 99%

A Unique Cellular and Molecular Microenvironment Is Present in Tertiary Lymphoid Organs of Patients with Spontaneous Prostate Cancer Regression

et al. 2017

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ObjectiveMultiple solid cancers contain tertiary lymphoid organs (TLO). However, it is unclear whether they promote tumor rejection, facilitate tumor evasion, or simply whether they are a byproduct of chronic inflammation. We hypothesize that although chronic inflammation induces TLO formation, the tumor milieu can modulate TLO organization and functions in prostate cancer. Therefore, our study seeks to elucidate the cellular and molecular signatures in unique prostatectomy specimens from evanescent carcinoma patients to identify markers of cancer regression, which could be harnessed to modulate local immunosuppression or potentially enhance TLO function.MethodsWe used multicolor immunofluorescence to stain prostate tissues, collected at different stages of cancer progression (prostatic intraepithelial neoplasia, intermediate and advanced cancer) or from patients with evanescent prostate carcinoma. Tissues were stained with antibodies specific for pro-inflammatory molecules (cyclooxygenase 2, CXCL10, IL17), tumor-infiltrating immune cells (mature DC-LAMP+ dendritic cells, CD3+ T cells, CD3+Foxp3+ regulatory T cells (Treg), T bet+ Th1 cells, granzyme B+ cytotoxic cells), and stromal cell populations (lymphatic vessels, tumor neovessels, high endothelial venules (HEV), stromal cells), which promote prostate tumor growth or are critical components of tumor-associated TLO.ResultsGenerally, inflammatory cells are located at the margins of tumors. Unexpectedly, we found TLO within prostate tumors from patients at different stages of cancer and in unique samples from patients with spontaneous cancer remission. In evanescent prostate carcinomas, accumulation of Treg was compromised, while Tbet+ T cells and CD8 T cells were abundant in tumor-associated TLO. In addition, we found a global decrease in tumor neovascularization and the coverage by cells positive for cyclooxygenase 2 (COX2). Finally, consistent with tumor regression, prostate stem cell antigen was considerably reduced in TLO and tumor areas from evanescent carcinoma patients.ConclusionCollectively, our results suggest that COX2 and Treg are attractive therapeutic targets that can be harnessed to enhance TLO-driven tumor immunity against prostate cancer. Specially, the presence of HEV and lymphatics indicate that TLO can be used as a platform for delivery of cell-based and/or COX2 blocking therapies to improve control of tumor growth in prostate cancer.

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Another TLO in the Wall: Education and Control of T Cells in Atherosclerotic Arteries

Abstract: Atherosclerosis is a lipid-storage disease of arteries that is exacerbated by chronic inflammatory processes. In this issue of Immunity, Hu et al. (2015) demonstrate that T cell responses in atherosclerotic lesions are controlled in tertiary lymphoid organs in the arterial wall.

Cited by 2 publications

References 13 publications

The microvascular niche instructs T cells in large vessel vasculitis via the VEGF-Jagged1-Notch pathway

The microvascular niche instructs T cells in large vessel vasculitis via the VEGF-Jagged1-Notch pathway

A Unique Cellular and Molecular Microenvironment Is Present in Tertiary Lymphoid Organs of Patients with Spontaneous Prostate Cancer Regression

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