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Helper T-Lymphocytes in Cardiovascular Diseases
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Vinay Kumar, Sahil Gupta, Rachel Rosenzweig, Shyam S. Bansal
Pressure overload in rodents, mimicking increased afterload in humans, leads to nonischemic HF and is also associated with increased Th1 polarization72 and infiltration73. Studies have shown that cardiac fibroblasts and CCR2+ macrophages produce CXCL10 and to a lesser extent CXCL9, which attracts CXCR3+ Th1 cells into the failing heart25, suggesting a critical role of the CXCR3-CXCL9/CXCL10 pathway. T-cells in the fibrotic myocardium mainly produce IFNγ, suggesting that Th1 T-cells are the main drivers of cardiac fibrosis in nonischemic HF as well73. Through direct cell-cell contact with cardiac fibroblasts, Th1 T-cells induce TGF-β production and αSMA expression in cardiac fibroblasts to promote their transition into myofibro-blasts73. Thus, both ischemic and nonischemic cardiomyopathies are associated with alterations in the ratio of Th1 to Th2 cells, with chronic HF leading to increased Th1 expression that is proportional to the severity of HF74. An increased ratio of Th1 to Th2 T-cells is also associated with increased production of IFNγ and TNFα in chronic HF75,76.
Invasive Tests
Published in Vineet Relhan, Vijay Kumar Garg, Sneha Ghunawat, Khushbu Mahajan, Comprehensive Textbook on Vitiligo, 2020
Hemant Kumar Kar, Gunjan Verma
In a published study, authors investigated the potential biomarkers of disease activity directly in the skin of vitiligo subjects and healthy subjects. Patient skin was sampled via a modified suction-blister technique, allowing for minimally invasive, objective assessment of cytokines and T-cell infiltrates in the interstitial skin fluid. Measuring CXCL9 directly in the skin can be used for diagnosis and as an early marker of treatment response [5].
Chikungunya virus and Japanese encephalitis virus
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
The cell surface component of the initial viral/host interaction is unknown, but skin fibroblasts appear to be initial cells attacked. Monocyte-derived macrophages can also be infected experimentally, but other hematopoetic cells cannot. Once the virus infects the cell and replicates, release of the virus (causing cellular lysis) results in viremia. The innate immune system quickly responds, releasing interferons, cytokines, and chemokines (such as CXCL9 and CXCL10 to attract T cells and MCP-1 to attract monocytes and dendritic cells) to combat infection. Therefore, not surprisingly, fever clinically corresponds to viremia and cytokine release (especially IL-6), which lasts somewhere between one and six days. Infection then proceeds hematogenously to fibroblasts at other sites, namely joints, dermis, and muscle, where symptoms correlate. Virus is able to disseminate in tissues, where it can persist for months after inoculation [4] and where ongoing inflammation associates with chronicity of symptoms. Notably, persistently high levels of IL-6 have been associated with long-term arthralgias [5].
Interleukin-17 Promotes the Infiltration of CD8+ T Cells into the Brain in a Mouse Model for Alzheimer’s Disease
Published in Immunological Investigations, 2023
Xiaoyang Ye, Ju Chen, Jie Pan, Qi Wu, Yue Wang, Mengqian Lu, Chengrong Zhang, Zhenzhen Zhang, Muyan Ma, Jinyong Zhu, Anthony T. Vella, Jun Wan, Kepeng Wang
CXCL9 and 10 bind to CXCR3 and attract the infiltration of T cells, neutrophils, NK cells, and monocytes (Muller et al. 2010; Tokunaga et al. 2018). Given the role of IL-17 in activating CXCL9/10 production in APP/PS1 mouse brains, we proposed that IL-17 promotes the infiltration of T cells and monocytes in response to Aβ accumulation. To this end, we performed flow cytometry analysis from APP/PS1 and WT mice that harbor intact or defective IL-17 signaling circuitry. The gating strategies to identify lymphocytes, invading macrophages, and microglia are shown in Figure S4a. Increased frequencies of CD11b- CD45hi lymphocytes, CD8+ T lymphocytes, and Gr1+CD11bintCD45int myeloid cells in the cortex and hippocampus were found in 15- and 24-month-old APP/PS1 mice when compared with age-matched wild type controls (Figure 4a). Loss of IL-17RA in APP/PS1 mice resulted in markedly reduced numbers of these cell populations (Figure 4a,c). Loss of IL-17 signaling in APP/PS1 mice did not result in gross abnormality of different blood cell populations in the blood or spleen (Figure S4b). The reduction of CD8+ T cells and Gr1+ CD11bint CD45int monocytes in the brain of IL-17RA knockout mice may thus be due to reduced migration from the periphery. Previous studies have shown that T cells can be attracted to and activated at the choroid plexus (CP), then cross the CP epithelium into the cerebral spinal fluid (CSF) (Kaur et al. 2016). It is possible that IL-17 promotes migration of T cells through the CP-CSF route.
Chemokine switch regulated by TGF-β1 in cancer-associated fibroblast subsets determines the efficacy of chemo-immunotherapy
Published in OncoImmunology, 2022
Angélique Vienot, Jean-René Pallandre, Elodie Renaude, Julien Viot, Adeline Bouard, Laurie Spehner, Marie Kroemer, Syrine Abdeljaoued, Bas van der Woning, Hans de Haard, Romain Loyon, Eric Hervouet, Paul Peixoto, Christophe Borg
CXCL14, as well as CXCL12, promotes idiopathic pulmonary fibrosis through CXCR4.38 Of note, a CXCR4 antagonist (BL-8040) in combination with chemo-immunotherapy induced an ORR of 32% in patients with metastatic PDAC.39 This association also increased CD8+ effector T cell tumor infiltration and decreased circulating Treg. CXCL9/10 are upregulated by cytokine stimulation in cancer cells, monocytes, endothelial cells, as well as in CAF.40–42 Reprogramming CAF gene expression in order to restore CXCL9/10 expression could also be an attractive approach to promote ICI efficacy. Recent data from preclinical studies support this strategy, particularly through NOX4 inhibition.43 An epigenetic reprogramming may predominantly target the expression of these chemokines30 and contribute to immunotherapy resistance. In our study, G9a and EZH2 were identified as the targeted enzymes by UNC0638 and GSK343, respectively, preventing the effect of TGF-β1 on the induction of CXCL9/10 in CAF. Other epigenetic factors than those associated with TGF-β1 have been implicated in CXCL9 transcriptional regulation, such as LIF.14,44 In addition, hypomethylation-mediated activation of IRX1 positively regulates CXCL14/NF-κB signaling to promote metastatic activities in osteosarcoma.45 However, ACKR2, NOX4, and IRX1 are not correlated with CXCL9/10/14 expression in CAF from our experiments (data not shown).
Immunotherapy for castration-resistant prostate cancer: has its time arrived?
Published in Expert Opinion on Biological Therapy, 2020
Several key cell types and soluble factors come to light when considering the active cell types within the intratumoral milieu. These include Treg, Th17, inhibitory macrophages, IL-6, and even RANK-Ligand, the latter produced by activated T cells and osteocytes. Rank-Ligand can also target dendritic cells to promote antigen presentation [11]. The most common goal is trying to improve the intratumoral milieu to make the tumor become the proverbial ‘hot’ or ‘bland’ site. A number of preclinical observations have been offered suggesting that the intratumoral milieu can be ‘corrected’ [19–22]. These have demonstrated that tumors can also disrupt chemokine expression and ‘deregulate’ the immune response. Also noted is that tumors that lack CD8 + T cells also have a reduction in the chemokines necessary for the recruitment of T cells that effect killing. In man, CXCR3 on CD8 + T cells may have decreased production that results in ‘non-inflamed’ or ‘cold’ tumors. It should also be kept in mind that the tumor cells themselves can produce CXCL9 and CXCL10. Observations in pancreatic cancer also confirm the role of these chemokines in contributing to an immunosuppressive environment.