interleukin 7
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2022 ◽  
pp. clincanres.0947.2021
Author(s):  
Jian L. Campian ◽  
Subhajit Ghosh ◽  
Vaishali Kapoor ◽  
Ran Yan ◽  
Sukrutha Thotala ◽  
...  

2022 ◽  
Author(s):  
Rayner M. L. Queiroz ◽  
Siân Piper ◽  
Johanna Susan Rees ◽  
Sam Strickson ◽  
Emmanuel Briend ◽  
...  

The ability of the cellular immune system to discriminate self from foreign antigens depends on the appropriate calibration of the T-cell receptor (TCR) signalling threshold. The lymphocyte homeostatic cytokine interleukin 7 (IL-7) is known to affect TCR thresholding, but the molecular mechanism is not fully elucidated. A better understanding of this process is highly relevant in the context of autoimmune disease therapy and cancer immunotherapy. We sought to characterise the early signalling events attributable to IL-7 priming; in particular, the altered phosphorylation of signal transduction proteins and their molecular localisation to the TCR. By integrating high-resolution proximity- phospho-proteomic and imaging approaches using primary T cells, rather than engineered cell lines or an in vitro expanded T cell population, we uncovered transduction events previously not linked to IL-7. We show that IL-7 leads to dephosphorylation of cytohesin interacting protein (CYTIP) at a hitherto undescribed phosphorylation site (pThr280) and alters the co-localisation of cytohesin 1 with the TCR and LFA-1 integrin. These results show that IL-7, acting via CYTIP and cytohesin-1, may impact TCR activation thresholds by enhancing the co-clustering of TCR and LFA-1 integrin.


2021 ◽  
Vol 12 ◽  
Author(s):  
Juan Huang ◽  
Zhiyao Long ◽  
Renyong Jia ◽  
Mingshu Wang ◽  
Dekang Zhu ◽  
...  

Interleukin-7 (IL-7) is produced by stromal cells, keratinocytes, and epithelial cells in host tissues or tumors and exerts a wide range of immune effects mediated by the IL-7 receptor (IL-7R). IL-7 is primarily involved in regulating the development of B cells, T cells, natural killer cells, and dendritic cells via the JAK-STAT, PI3K-Akt, and MAPK pathways. This cytokine participates in the early generation of lymphocyte subsets and maintain the survival of all lymphocyte subsets; in particular, IL-7 is essential for orchestrating the rearrangement of immunoglobulin genes and T-cell receptor genes in precursor B and T cells, respectively. In addition, IL-7 can aid the activation of immune cells in anti-virus and anti-tumor immunity and plays important roles in the restoration of immune function. These biological functions of IL-7 make it an important molecular adjuvant to improve vaccine efficacy as it can promote and extend systemic immune responses against pathogens by prolonging lymphocyte survival, enhancing effector cell activity, and increasing antigen-specific memory cell production. This review focuses on the biological function and mechanism of IL-7 and summarizes its contribution towards improved vaccine efficacy. We hope to provide a thorough overview of this cytokine and provide strategies for the development of the future vaccines.


2021 ◽  
Vol 8 ◽  
Author(s):  
Franziska Diekmann ◽  
Ekaterina Legchenko ◽  
Philippe Chouvarine ◽  
Ralf Lichtinghagen ◽  
Harald Bertram ◽  
...  

Objectives: Interleukin-7 (IL-7) secures B cell maturation, regulatory T and natural killer (NK) cell survival, and homeostasis, all of which are important for beneficial immunomodulation in pulmonary arterial hypertension (PAH). However, the role and potential impact of IL-7, VEGF-C and the vascular injury markers ICAM-1, and VCAM-1 on the pathobiology and severity of PAH is unknown.Methods: EDTA blood was collected during cardiac catheterization from the superior vena cava (SVC), pulmonary artery (PA), and ascending aorta (AAO) in children with pulmonary hypertension (PH) [n = 10; 9.1 (3.9–18.5) years] and non-PH controls [n = 10; 10.5 (2.0–17.3) years]. Compartment-specific plasma concentrations of IL-7, VEGF-C, aldosterone, ICAM-1, and VCAM-1 were determined using Meso Scale Discovery's multi array technology and the LIAISON Aldosterone Assay.Results: Children with PH had approximately 50% lower IL-7 (p < 0.01) and 59% lower VEGF-C plasma levels (p < 0.001) in the SVC, PA, and AAO versus non-PH controls. IL-7 and VEGF-C concentrations negatively correlated with the pulmonary vascular resistance (PVR)/systemic vascular resistance (SVR) ratio (rho = −0.51 and r = −0.62, respectively). Central-venous IL-7 strongly positively correlated with VEGF-C (r = 0.81). Most patients had a step down in ICAM-1 and VCAM-1 plasma concentrations across the pulmonary circulation and both ICAM-1 and VCAM-1 transpulmonary gradients negatively correlated with invasive hemodynamics.Conclusion: This manuscript is the first report on decreased circulating IL-7 and VEGF-C plasma concentrations in human PAH and their inverse correlations with invasive surrogates of PAH severity. Additional and larger studies are needed to explore the role of the immune-modulatory IL-7 and VEGF-C in pediatric and adult PAH.


2021 ◽  
Vol 12 ◽  
Author(s):  
Deng Chen ◽  
Ting-Xuan Tang ◽  
Hai Deng ◽  
Xiang-Ping Yang ◽  
Zhao-Hui Tang

Interleukin-7 (IL-7), a molecule known for its growth-promoting effects on progenitors of B cells, remains one of the most extensively studied cytokines. It plays a vital role in health maintenance and disease prevention, and the congenital deficiency of IL-7 signaling leads to profound immunodeficiency. IL-7 contributes to host defense by regulating the development and homeostasis of immune cells, including T lymphocytes, B lymphocytes, and natural killer (NK) cells. Clinical trials of recombinant IL-7 have demonstrated safety and potent immune reconstitution effects. In this article, we discuss IL-7 and its functions in immune cell development, drawing on a substantial body of knowledge regarding the biology of IL-7. We aim to answer some remaining questions about IL-7, providing insights essential for designing new strategies of immune intervention.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Afonso R. M. Almeida ◽  
João L. Neto ◽  
Ana Cachucho ◽  
Mayara Euzébio ◽  
Xiangyu Meng ◽  
...  

AbstractInterleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemic stage in which B-cell precursors display self-renewal ability, initiating leukemia resembling PAX5 P80R or Ph-like human B-ALL. Full transformation associates with transcriptional upregulation of oncogenes such as Myc or Bcl2, downregulation of tumor suppressors such as Ikzf1 or Arid2, and major IL-7R signaling upregulation (involving JAK/STAT5 and PI3K/mTOR), required for leukemia cell viability. Accordingly, maximal signaling drives full penetrance and early leukemia onset in homozygous IL7R mutant animals. Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are potential treatment avenues for IL-7R-related cases. Our model, a resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.


2021 ◽  
Vol 12 ◽  
Author(s):  
Kaushik Sen ◽  
Sudeshna Datta ◽  
Arup Ghosh ◽  
Atimukta Jha ◽  
Abdul Ahad ◽  
...  

The response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely impacted by the level of virus exposure and status of the host immunity. The nature of protection shown by direct asymptomatic contacts of coronavirus disease 2019 (COVID-19)-positive patients is quite intriguing. In this study, we have characterized the antibody titer, SARS-CoV-2 surrogate virus neutralization, cytokine levels, single-cell T-cell receptor (TCR), and B-cell receptor (BCR) profiling in asymptomatic direct contacts, infected cases, and controls. We observed significant increase in antibodies with neutralizing amplitude in asymptomatic contacts along with cytokines such as Eotaxin, granulocyte-colony stimulating factor (G-CSF), interleukin 7 (IL-7), migration inhibitory factor (MIF), and macrophage inflammatory protein-1α (MIP-1α). Upon single-cell RNA (scRNA) sequencing, we explored the dynamics of the adaptive immune response in few representative asymptomatic close contacts and COVID-19-infected patients. We reported direct asymptomatic contacts to have decreased CD4+ naive T cells with concomitant increase in CD4+ memory and CD8+ Temra cells along with expanded clonotypes compared to infected patients. Noticeable proportions of class switched memory B cells were also observed in them. Overall, these findings gave an insight into the nature of protection in asymptomatic contacts.


Author(s):  
Ren Fen Chen ◽  
Nady Braidy ◽  
Ying Hua Xu ◽  
Sarah Tan ◽  
Daniel Kam Yin Chan

<b><i>Introduction:</i></b> Little is known about the role of inflammation in the process of small vessel vascular dementia (VaD). Recently, the notion that small vessel VaD is caused solely by vascular pathology has been challenged by new evidence of concomitant breakdown of the blood-brain barrier and dysregulation of neuroinflammation in the white matter. <b><i>Methods:</i></b> We examined selected inflammatory cytokines and chemokines in the plasma from patients with small vessel VaD (<i>n</i> = 41) and from age-matched controls (<i>n</i> = 131) using multiplex bead-based assays. Participants were recruited from a memory disorder clinic and from a hospital or community. <b><i>Results:</i></b> When compared to controls, patients with small vessel VaD had a highly significant increase in the plasma interferon-γ-inducible protein 10 (IP-10) level (<i>p</i> &#x3c; 0.0001) and a highly significant decrease in plasma macrophage inflammatory protein 1-beta (MIP-1β) level (<i>p</i> &#x3c; 0.0001). We also observed a significant increase in patients’ levels of interleukin-10 (IL-10) (<i>p</i> = 0.022) as well as decreases in interleukin-8 (IL-8) (<i>p</i> = 0.004) and interleukin-7 (IL-7) (<i>p</i> = 0.011) when compared to age-matched controls. <b><i>Conclusion:</i></b> Both IP-10 and MIP-1β are macrophage-related chemokines. The significant differences between cases and controls suggest a potential role for macrophages in small vessel VaD neuroinflammation. Although it remains unclear whether there is a causal effect of their alteration for small vessel VaD, a better understanding of these molecules in the pathogenesis of small vessel VaD may lead to improved diagnosis and future treatment outcomes against this disease.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1715-1715
Author(s):  
Ryan Urak ◽  
Ashlie Munoz ◽  
Hui-Ju Hsieh ◽  
Ellie Taus ◽  
Stephen J Forman ◽  
...  

Abstract Dexamethasone (Dex) has been a mainstay for the treatment of inflammatory pathologies, such as in autoimmunity and cytokine release syndrome (CRS) from immunotherapies. However, its effects on chimeric antigen receptor (CAR) T cells, during CRS events have not been interrogated. In this study, we treated the CAR T cells with different concentrations of Dex (0, 1, and 10µM) single or multiple times in vitro and expanded them for one week. We demonstrated that Dex treatment did not inhibit CAR T cell growth and functionality even with concentrations higher than what would be used in the clinic. Interestingly, we observed that the Dex treatment significantly upregulated endogenous gamma chain cytokine receptor-interleukin 7 receptor alpha (IL7Rα) at the mRNA and protein levels (P=0.0005) (Fig 1a). These effects are not T cell subset dependent because we observed upregulation of IL7Rα on PBMC and enriched naïve and memory T cell-derived CAR T cells. Furthermore, un-transduced T cells also exhibited IL7Rα increase, which suggests that the upregulation of IL7Rα is the general mechanism of Dex for T cells. IL7Rα is well accepted as a key element to CAR T cell persistence and memory T cell formation. However, the IL7R-IL-7 signaling pathway is limited due to the downregulation of high-affinity IL7Rα during the activation and expansion of CAR T cells. We found out that Dex can upregulate endogenous IL7Rα in a reversible manner, which is an important factor for safety in clinical application. We showed that ex vivo upregulation of IL7Ra by a single Dex treatment subsequently enhanced CAR T cell persistence and anti-tumor efficacy in vivo in the presence of IL-7. To further confirm the positive effects of Dex on CAR T cell therapy, we performed a combinatorial therapy by delivering CD19 CAR T cells to acute lymphoid leukemia (ALL) tumor-bearing NOD-scid IL2Rgammanull (NSG) mice and then administering Dex (1mg/kg) and IL-7-expressing CHO cells. Consistently, we observed a complete cure of tumor-bearing mice only in the CD19 CAR T cell group that was given both Dex and IL-7, but not CAR alone and Dex only groups (Fig 1b-c) (P=0.0006). Mice survived, tumor-free, over 150 days. Supportively, we observed CAR T cell persistence only in the CAR T cells combined with Dex and IL7 group but not in the CAR group. To determine if Dex influenced CAR T cells beyond IL7Rα, we performed gene analysis and demonstrated that IL7Rα, but not other γ chain cytokines was selectively upregulated by Dex, which supports previous reports from Lee et al. that Dex and glucocorticoid receptors (GR) complex binds upstream of the IL-7rα promoter preferentially regulating IL7Rα. Furthermore, we utilized Nanostring technology to analyze CAR T cells with and without Dex treatment for mRNA signatures that related to signaling pathways. We observed pathways related to activation, migration, persistence, and chemokine production were upregulated, while pathways related to apoptosis and TCR diversity were downregulated after Dex treatment. The results indicated that Dex may regulate multiple functions of CAR T cells. Overall, our studies in both in vitro and in vivo treatment support that Dex does not have negative effects on CAR T cell potency but provides insight into an unforeseen strategy to improve CAR T cell therapies through upregulation of IL-7Rα and improving T cell activation, trafficking, and persistence. We believe our observations could extend beyond hematological malignancies to a potentially potent and durable therapy for solid tumors, as Dex is not only an immunosuppressive agent but also an anti-cancer drug used against a multitude of tumors to prevent tumor growth as well as modulate the microenvironment. Our data also provided rationale on starting CAR T cell therapy without the necessity of tapering off the ongoing steroid treatment. Figure 1 Figure 1. Disclosures Forman: Allogene: Consultancy; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company. Wang: Pepromene Bio, Inc.: Consultancy.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi50-vi50
Author(s):  
Jian Campian ◽  
Omar Butt ◽  
Jingqin Luo ◽  
Chandini Avvaru ◽  
Ruth Katumba ◽  
...  

Abstract BACKGROUND Lymphopenia is common after standard radiation therapy (RT) and temozolomide (TMZ) in high-grade gliomas (HGG) and correlates with shorter survival. Interleukin-7 (IL-7), a T-cell proliferation cytokine, is inappropriately low in HGG patients. Our previous preclinical studies demonstrated that NT-I7 (efineptakin alfa), a recombinant human IL-7, corrects lymphopenia and improves survival in murine glioma models. This study examines the safety and absolute lymphocyte counts (ALCs) following administration of NT-I7 patients with newly diagnosed HGG. METHODS Patients with HGG receiving RT/TMZ with ALC ≥600 were eligible. NT-I7 was administered intramuscularly within 1 week after completion of concurrent RT/TMZ and then every 12 weeks, for up to 4 total doses. Phase I examined 6 dose levels (60, 120, 240, 540, 720, and 960 mcg/kg) using the accelerated-titration design for the first 2 doses and 3 + 3 design thereafter to identify the maximum tolerated dose (MTD). Phase II is a double-blinded, placebo-controlled study with 10 HGG patients per arm comparing changes in ALC. Immune profiling will be performed with CyTOF and cytokine analysis. RESULTS Phase I is complete, with 19 patients (89% GBM, median age: 58 (range: 25-78), median baseline ALC: 1000 cells/mm3, median dexamethasone: 0 mg/day (range: 0-12)). The median number of NT-I7 doses administered was 2 (range: 2-4). The most common treatment-related adverse event was grade 1 or 2 injection site reactions (42%). Two patients had dose-limiting toxicities at 960 mcg/kg (grade 3 elevated alanine aminotransferase and grade 3 back pain), prompting selection of 720 mcg/kg for phase II. Dose-dependent increases in ALC were observed at 4 weeks ranging from 1.3x to 4.1x. Phase II enrollment is ongoing. CONCLUSIONS NT-I7 is well tolerated when administered after chemoradiotherapy for HGG patients with MTD of 720 mcg/kg and demonstrates dose-dependent increase of ALC. Phase II and immune profiling are ongoing. Clinical Trial ID: NCT03687957.


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