helper t cell
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2021 ◽  
Author(s):  
James R Michels ◽  
Mohammad Shaheed Nazrul ◽  
Sudeep Adhikari ◽  
Dawn Wilkins ◽  
Ana B Pavel

A predominant source of complication in SARS-CoV-2 patients arises from the cytokine storm, an elevated expression of inflammatory helper T-cell associated cytokines that can lead to tissue damage and organ failure. The high inflammatory burden of this viral infection often results in cardiovascular comorbidities. A better understanding of the interaction between the cytokine storm and cardiovascular proteins might inform medical decisions and therapeutic approaches. We hypothesized that all major helper T-cell inflammatory pathways (Th1, Th2 and Th17) synergistically contribute to cardiometabolic modifications in serum of COVID-19 patients. We proved our hypothesis by integrating Th1, Th2 and Th17 cytokines to predict expression of cardiometabolic proteins profiled by OLINK proteomics.


2021 ◽  
Vol 118 (43) ◽  
pp. e2108376118
Author(s):  
Da-Sol Kuen ◽  
Miso Park ◽  
Heeju Ryu ◽  
Garam Choi ◽  
Young-Hye Moon ◽  
...  

GPCR-Gα protein–mediated signal transduction contributes to spatiotemporal interactions between immune cells to fine-tune and facilitate the process of inflammation and host protection. Beyond this, however, how Gα proteins contribute to the helper T cell subset differentiation and adaptive response have been underappreciated. Here, we found that Gα13 signaling in T cells plays a crucial role in inducing follicular helper T (Tfh) cell differentiation in vivo. T cell–specific Gα13-deficient mice have diminished Tfh cell responses in a cell-intrinsic manner in response to immunization, lymphocytic choriomeningitis virus infection, and allergen challenges. Moreover, Gα13-deficient Tfh cells express reduced levels of Bcl-6 and CXCR5 and are functionally impaired in their ability to adhere to and stimulate B cells. Mechanistically, Gα13-deficient Tfh cells harbor defective Rho-ROCK2 activation, and Rho agonist treatment recuperates Tfh cell differentiation and expression of Bcl-6 and CXCR5 in Tfh cells of T cell–specific Gα13-deficient mice. Conversely, ROCK inhibitor treatment hampers Tfh cell differentiation in wild-type mice. These findings unveil a crucial regulatory role of Gα13-Rho-ROCK axis in optimal Tfh cell differentiation and function, which might be a promising target for pharmacologic intervention in vaccine development as well as antibody-mediated immune disorders.


2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hong Ki Min ◽  
Sehee Kim ◽  
Ji-Yeon Lee ◽  
Kyoung-Woon Kim ◽  
Sang-Heon Lee ◽  
...  

Abstract Background Patients with rheumatoid arthritis (RA) have increased levels of interleukin-18 (IL-18) and decreased levels of IL-18 binding protein (IL-18BP) in the serum and synovial fluid (SF) compared to those in patients with osteoarthritis (OA) or in healthy controls. In this study, we evaluated the effects of IL-18BP on osteoclastogenesis and T cell differentiation in RA in vitro. Methods Serum and SF of patients with RA and OA were collected to compare IL-18 and IL-18BP levels by the enzyme-linked immunosorbent assay. Peripheral blood mononuclear cells (PBMCs) and SF mononuclear cells (SFMCs) of RA patients were cultured under type 17 helper T cell (Th17) polarisation conditions with or without IL-18BP. In addition, PBMCs were cultured in the presence of receptor activator of nuclear factor kappa-Β ligand (RANKL) or IL-17A with or without IL-18BP, and tartrate-resistant acid phosphatase (TRAP) staining and real-time quantitative polymerase chain reaction for expression levels of osteoclast-related genes were performed. Results IL-18 levels were higher in the serum and SF of patients with RA, whereas IL-18BP was lower in the SF of patients with RA than in the control group. Treatment of patients’ PBMCs with IL-18BP decreased the differentiation of CD4+ IL-17A+ and CD4+ RANKL+ T cells, whereas the differentiation of CD4+CD25highFOXP3+ T cell population increased in a dose-dependent manner. These changes in CD4+ T cell differentiation were also observed in the SFMCs of patients with RA. The levels IL-17A and soluble RANKL in the culture medium were significantly decreased by IL-18BP. IL-18BP administration decreased TRAP+ cell counts in a dose-dependent manner on the background of stimulation with RANKL-and IL-17A. In addition, expression levels of TRAP, NFATC1, CTSK, and TNFRSF11A (RANK) genes were lower in the IL-18BP treated cells. Conclusion We showed that IL-18BP can rectify the Th17/Treg imbalance and decrease IL-17-induced osteoclastogenesis in PBMCs from patients with RA. Therefore, IL-18BP may have therapeutic potential for RA treatment.


FEBS Open Bio ◽  
2021 ◽  
Author(s):  
Yusuke Suzuki ◽  
Tomoya Hayashi ◽  
Ryoma Yokoyama ◽  
Fumika Nakagawa ◽  
Joe Inoue ◽  
...  

Author(s):  
Yunbo Gao ◽  
Jingyun Li ◽  
Jian Jiao ◽  
Ying Li ◽  
Chengshuo Wang ◽  
...  

<b><i>Background:</i></b> Tumor protein p63 has been shown to be important for epithelial dysfunction, including epithelial barrier defects and mucosal inflammation, in the development of chronic rhinosinusitis with nasal polyps (CRSwNP). Basonuclin1 (BNC1), an epithelial-specific transcriptional factor, is a direct downstream target of p63 and thus might be involved in the pathogenesis of CRSwNP. <b><i>Objective:</i></b> We sought to investigate whether BNC1 was associated with p63-mediated epithelial barrier defects and nasal mucosal inflammation in CRSwNP. <b><i>Methods:</i></b> Nasal tissue biopsies were obtained from 91 patients to CRSwNP, 49 chronic rhinosinusitis without nasal polyps (CRSsNP) patients, and 28 control subjects. Immunohistochemistry and immunofluorescence staining were used to determine the distribution of BNC1 in tissues and localization in cells, respectively. Quantitative PCR was performed to detect the expression levels of <i>BNC1</i>, <i>TP63</i>, epithelial barrier proteins, and type-2 helper T-cell inflammation-related genes. <b><i>Results:</i></b> <i>BNC1</i> mRNA expression was significantly elevated in the tissues in CRSwNP patients compared with CRSsNP (1.96-fold, <i>p</i> = 0.0003) and control groups (2.40-fold, <i>p</i> &#x3c; 0.0001). <i>BNC1</i> staining was strongly positive in the nasal epithelium and co-localized with p63-positive epithelial cells. The expression of <i>BNC1</i> mRNA was strongly correlated with <i>TP63</i> mRNA level both in tissue biopsies (<i>r</i> = 0.78, <i>p</i> &#x3c; 0.0001) and epithelial scrapings (<i>r</i> = 0.97, <i>p</i> &#x3c; 0.0001). <i>BNC1</i> expression was also positively correlated with epithelial barrier protein genes (<i>CDH1</i>, <i>CLDN1</i>, <i>CLDN4</i>, <i>TJP1,</i> and <i>TJP2</i>) and epithelial genes involved in T<sub>H</sub>2 inflammation (<i>IL33</i>, <i>CCL26</i>, <i>CLC</i>, and <i>ALOX15</i>). <b><i>Conclusions:</i></b> Overexpression of <i>BNC1</i> may be associated with increased expression of <i>TP63</i>, and possibly contribute to the epithelial barrier defects and T<sub>H</sub>2 inflammation in CRSwNP.


Author(s):  
Paula Bousquet ◽  
Sebastian Meltzer ◽  
Anniken Fuglestad ◽  
Torben Lüders ◽  
Ying Esbensen ◽  
...  

A significant percentage of colorectal cancer patients proceeds to metastatic disease. We hypothesised that mitochondrial DNA (mtDNA) polymorphisms, generated by the high mtDNA mutation rate of energy-demanding clonal immune cell expansions and assessable in peripheral blood, reflect how efficiently systemic immunity impedes metastasis. We studied 44 rectal cancer patients from a population-based prospective biomarker study, given curative-intent neoadjuvant radiation and radical surgery for high-risk tumour stage and followed for metastatic failure. Blood specimens were sampled at the time of diagnosis and analysed for the full-length mtDNA sequence, composition of immune cell subpopulations and damaged serum mtDNA. A high mtDNA variant number, coexisting with an mtDNA non-H haplogroup, was associated with low risk of a metastatic event. Abundant mtDNA variants correlated with proliferating helper T cells and cytotoxic effector T cells in the circulation. Patients without metastatic progression had high relative levels of circulating tumour-targeting effector and natural killer T cells and, of note, the naïve (LAG-3+) helper T cell population, all inversely correlated with cell-free damaged mtDNA in serum known to cause antagonising inflammation. The statistical associations suggested that patient’s constitutional mtDNA manifests the helper T cell capacity to mount immunity that controls metastatic susceptibility.


2021 ◽  
Author(s):  
Michael Hiltensperger ◽  
Eduardo Beltrán ◽  
Ravi Kant ◽  
Sofia Tyystjärvi ◽  
Gildas Lepennetier ◽  
...  

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