It’s all about the CD3+ T-cells: how circulating immune cell subset analyses can predict early relapse in Hodgkin lymphoma

2019 ◽  
Vol 60 (10) ◽  
pp. 2345-2347
Author(s):  
Jonathan Moreira ◽  
Leonidas C. Platanias ◽  
Kehinde U. A. Adekola
Keyword(s):  
T Cells ◽  
Hodgkin Lymphoma ◽  
Immune Cell ◽  
Cell Subset ◽  
Immune Cell Subset ◽  
Early Relapse

scholarly journals P060 The pharmacologic inhibition of store-operated calcium entry pathway in inflammatory bowel disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S164-S165
Author(s):  
M Letizia ◽  
C Yerinde ◽  
A Sand ◽  
S Schlickeiser ◽  
U Kaufmann ◽  
...  
Keyword(s):  
T Cells ◽  
Lamina Propria ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Cell Subset ◽  
Mass Cytometry ◽  
Immune Cell Subset ◽  
Store Operated Calcium Entry ◽  
Inflammatory Bowel ◽  
And Function

Abstract Background Store-operated calcium entry (SOCE) represents the major calcium influx pathway in T cells which not only controls the activation and function of lymphocytes, but which also has been implicated in the metabolic homeostasis and survival of murine CD4+ and CD8+ T cells. Conditional knockout mice, in which SOCE signalling components are deleted in T cells, revealed that SOCE is required for the induction of intestinal inflammation in mouse models of colitis. However, the effects of SOCE inhibition have not been studied in inflammatory bowel disease (IBD) and it remains elusive, which immune cell subset is affected by the pharmaceutical blockade of SOCE. We therefore aim to investigate the effects of SOCE inhibitor BTP-2 on functions and metabolic homeostasis of human lymphocytes isolated from IBD patients. Methods PBMC and/or lamina propria lymphocytes were isolated from colitis patients undergoing colon resection and mass cytometry served in order to evaluate the cytokine production and activation of B, T, NK as well as myeloid cells. Additionally, Ca2+ influx measurement and Seahorse analyses were performed in order to assess the metabolic status of immune cell subsets after SOCE inhibition. Results Data on B, T, NK, myeloid cells and neutrophils isolated from peripheral blood or colon lamina propria revealed that each immune cell subset harbours a distinctive SOCE-dependent Ca2+ influx rate, suggesting that SOCE might differentially regulate the activation and function of each cell subtype. In particular, CD4+ and CD8+ T cells, B and NK cells as well as monocytes were highly susceptible to extracellular Ca2+ influx, followed by granulocytes. Furthermore, inhibition of SOCE in lymphocytes resulted in impaired metabolic fitness, reduced glycolytic capacity and impaired fatty acid oxidation. Finally, BTP-2 was able to decrease the production of key pro-inflammatory cytokines involved in IBD, including TNFα and IL-17 in lamina propria resident T cells. Conclusion Our data revealed for the first time that the cytokine production and the activation of several immune cell subtypes can be modulated by SOCE blockade in human intestinal inflammation, identifying SOCE as a novel therapeutic target in colitis. Moreover, we hope that a wide phenotypical characterisation of immune cells via mass cytometry will provide a better insight into positive as well as negative effects of SOCE inhibitors that might interfere with the clinical applicability of SOCE inhibitors for treating IBD.

scholarly journals Single-cell profiling reveals the importance of CXCL13/CXCR5 axis biology in lymphocyte-rich classic Hodgkin lymphoma

2021 ◽  
Vol 118 (41) ◽  
pp. e2105822118
Author(s):  
Tomohiro Aoki ◽  
Lauren C. Chong ◽  
Katsuyoshi Takata ◽  
Katy Milne ◽  
Ashley Marshall ◽  
...  
Keyword(s):  
T Cells ◽  
Single Cell ◽  
Hodgkin Lymphoma ◽  
Immune Cell ◽  
Cell Subset ◽  
Progression Free Survival ◽  
Tissue Microarrays ◽  
Classic Hodgkin Lymphoma ◽  
Reactive Lymph Node ◽  
Technical Advances

Lymphocyte-rich classic Hodgkin lymphoma (LR-CHL) is a rare subtype of Hodgkin lymphoma. Recent technical advances have allowed for the characterization of specific cross-talk mechanisms between malignant Hodgkin Reed-Sternberg (HRS) cells and different normal immune cells in the tumor microenvironment (TME) of CHL. However, the TME of LR-CHL has not yet been characterized at single-cell resolution. Here, using single-cell RNA sequencing (scRNA-seq), we examined the immune cell profile of 8 cell suspension samples of LR-CHL in comparison to 20 samples of the mixed cellularity (MC, 9 cases) and nodular sclerosis (NS, 11 cases) subtypes of CHL, as well as 5 reactive lymph node controls. We also performed multicolor immunofluorescence (MC-IF) on tissue microarrays from the same patients and an independent validation cohort of 31 pretreatment LR-CHL samples. ScRNA-seq analysis identified a unique CD4+ helper T cell subset in LR-CHL characterized by high expression of Chemokine C-X-C motif ligand 13 (CXCL13) and PD-1. PD-1+CXCL13+ T cells were significantly enriched in LR-CHL compared to other CHL subtypes, and spatial analyses revealed that in 46% of the LR-CHL cases these cells formed rosettes surrounding HRS cells. MC-IF analysis revealed CXCR5+ normal B cells in close proximity to CXCL13+ T cells at significantly higher levels in LR-CHL. Moreover, the abundance of PD-1+CXCL13+ T cells in the TME was significantly associated with shorter progression-free survival in LR-CHL (P = 0.032). Taken together, our findings strongly suggest the pathogenic importance of the CXCL13/CXCR5 axis and PD-1+CXCL13+ T cells as a treatment target in LR-CHL.

Phase II study of cixutumumab (IMC-A12) in thymic malignancies.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7033-7033 ◽  
Author(s):  
Arun Rajan ◽  
Gregory J. Riely ◽  
Corey Allan Carter ◽  
Anish Thomas ◽  
Sean Khozin ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cell ◽  
Mutational Analysis ◽  
High Titer ◽  
Cell Subset ◽  
Median Number ◽  
Effector Memory ◽  
Immune Cell Subset ◽  
Treatment Needs ◽  
Systemic Treatments

7033 Background: The IGF-1 receptor (IGF-IR) is expressed in thymoma (T) and thymic carcinoma (TC). Prolonged SD has been seen with anti-IGF-IR therapy in thymic tumors in phase I trials. Cixutumumab (C) is a fully human IgG1 monoclonal antibody (ab) that targets IGF-IR. Methods: Patients (pts) with recurrent T or TC, PS 0-2, measurable disease, and normal organ function received C at 20 mg/kg IV q3wks until progression or intolerable toxicity. Primary endpoint was response rate. Correlative studies included immune cell subset (central memory, effector memory, naïve and regulatory T cells), circulating endothelial progenitor (CEP) cell, serum IGF-1 and IGF-IR in PBMCs, anticytokine ab, and tumor mutational analysis. Results: Forty-five pts enrolled from two centers (20 female, T=33, med age 52 yrs, range, 26-86). Median number of prior systemic treatments: 3 (range, 1-11). Median number of cycles of C administered: 6 (range, 1-41). In 30 evaluable T pts there were 4 (13%) PR, 23 (77%) SD, and 3 (10%) PD. Corresponding numbers in 12 TC pts were 0, 5 (42%) and 7 (58%). Median PFS for T and TC was 40 and 9 wks respectively. C-related grade 3/4 AEs were hyperglycemia (8%), hyperuricemia, weight loss, lipase elevation, chest wall pain (5% each) and AST elevation (3%). Two pts died while on study: one due to respiratory insufficiency related to T after 5 cycles and one due to worsening myasthenia and an acute coronary event after 13 cycles. In 8 of 33 T pts autoimmune (AI) symptoms developed (4 new-onset) due to immune thrombocytopenic purpura, myositis, myocarditis, colitis, PRCA and food allergy. In the first 13 pts a trend towards increased numbers of central and effector memory T cells and a decrease in naïve T cells and CEPs was seen. High-titer anticytokine abs, including anti-IFNa, anti-IL-12, and anti-IL-17A, were found in 13/27 pts tested. No EGFR, KRAS or BRAF mutation, HER2 amplification or ALK translocations were detected in 11 tumors analyzed. Conclusions: C monotherapy is well tolerated and active in T. Accrual will continue until 37 T pts are enrolled. Activity in TC is unworthy of further investigation. CEP and immune cell subset analysis suggests therapy may impact angiogenesis and immune response. Development of AI symptoms during treatment needs further evaluation.

scholarly journals PD-1 and TIGIT coexpression identifies a circulating CD8 T cell subset predictive of response to anti-PD-1 therapy

2020 ◽  
Vol 8 (2) ◽  
pp. e001631
Author(s):  
Sylvain Simon ◽  
Valentin Voillet ◽  
Virginie Vignard ◽  
Zhong Wu ◽  
Camille Dabrowski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Therapeutic Response ◽  
Immune Cell ◽  
Expression Profiles ◽  
Cell Subset ◽  
Phenotypic Characterization ◽  
Multiparameter Flow Cytometry ◽  
Specific Gene

BackgroundClinical benefit from programmed cell death 1 receptor (PD-1) inhibitors relies on reinvigoration of endogenous antitumor immunity. Nonetheless, robust immunological markers, based on circulating immune cell subsets associated with therapeutic efficacy are yet to be validated.MethodsWe isolated peripheral blood mononuclear cell from three independent cohorts of melanoma and Merkel cell carcinoma patients treated with PD-1 inhibitor, at baseline and longitudinally after therapy. Using multiparameter flow cytometry and cell sorting, we isolated four subsets of CD8+ T cells, based on PD-1 and TIGIT expression profiles. We performed phenotypic characterization, T cell receptor sequencing, targeted transcriptomic analysis and antitumor reactivity assays to thoroughly characterize each of these subsets.ResultsWe documented that the frequency of circulating PD-1+TIGIT+ (DPOS) CD8+ T-cells after 1 month of anti-PD-1 therapy was associated with clinical response and overall survival. This DPOS T-cell population was enriched in highly activated T-cells, tumor-specific and emerging T-cell clonotypes and T lymphocytes overexpressing CXCR5, a key marker of the CD8 cytotoxic follicular T cell population. Additionally, transcriptomic profiling defined a specific gene signature for this population as well as the overexpression of specific pathways associated with the therapeutic response.ConclusionsOur results provide a convincing rationale for monitoring this PD-1+TIGIT+ circulating population as an early cellular-based marker of therapeutic response to anti-PD-1 therapy.

scholarly journals Label-free haemogram using wavelength modulated Raman spectroscopy for identifying immune-cell subset

2014 ◽  
Author(s):  
Praveen C. Ashok ◽  
Bavishna B. Praveen ◽  
Elaine C. Campbell ◽  
Kishan Dholakia ◽  
Simon J. Powis
Keyword(s):  
Raman Spectroscopy ◽  
Immune Cell ◽  
Cell Subset ◽  
Label Free ◽  
Immune Cell Subset

scholarly journals T cell subset-selective IL2RA enhancers shape autoimmune diabetes risk

2020 ◽  
Author(s):  
Dimitre R. Simeonov ◽  
Harikesh S. Wong ◽  
Jessica T. Cortez ◽  
Arabella Young ◽  
Zhongmei Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Regulatory T Cells ◽  
Disease Progression ◽  
Genetic Variants ◽  
Immune Cell ◽  
Disease Risk ◽  
Autoimmune Diabetes ◽  
Cell Subset ◽  
Regulatory Elements

The majority of genetic variants associated with complex human autoimmune diseases reside in enhancers1–3, non-coding regulatory elements that control gene expression. In contrast with variants that directly alter protein-coding sequences, enhancer variants are predicted to tune gene expression modestly and function in specific cellular contexts4, suggesting that small alterations in the functions of key immune cell populations are sufficient to shape disease risk. Here we tested this concept by experimentally perturbing distinct enhancers governing the high affinity IL-2 receptor alpha chain (IL2RA; also known as CD25). IL2RA is an immune regulator that promotes the pro- and anti-inflammatory functions of conventional T cells (Tconvs) and regulatory T cells (Tregs), respectively, and non-coding genetic variants in IL2RA have been linked to multiple autoimmune disorders4. We previously tiled across the IL2RA locus using CRISPR-activation and identified a stimulation-responsive element (CaRE4) with an enhancer that modestly affects the kinetics of IL2RA expression in Tconvs5. This enhancer is conserved across species and harbors a common human SNP associated with protection from Type 1 Diabetes (T1D)5,6. We now identified an additional conserved enhancer, termed CaRE3 enhancer, which modestly affected steady state IL2RA expression in regulatory T cells (Tregs). Despite their seemingly subtle impact on gene expression, the CaRE3 and CaRE4 enhancers had pronounced yet divergent effects on the incidence of diabetes in autoimmune prone animals. Deletion of the conserved CaRE4 enhancer completely protected against autoimmune diabetes even in animals treated with an immunostimulating anti-PD1 checkpoint inhibitor, whereas deletion of the CaRE3 enhancer accelerated spontaneous disease progression. Quantitative multiplexed imaging of the pancreatic lymph nodes (panLNs) revealed that each enhancer deletion preferentially affected the protein expression levels of IL2RA in activated Tconvs or Tregs, reciprocally tuning local competition for IL-2 input signals. In animals lacking the CaRE4 enhancer, skewed IL-2 signaling favored Tregs, increasing their local density around activated Tconvs to strongly suppress emergence of autoimmune effectors. By contrast, in animals lacking the CaRE3 enhancer, IL-2 signals were skewed towards activated Tconvs, promoting their escape from Treg control. Collectively, this work illustrates how subtle changes in gene regulation due to non-coding variation can significantly alter disease progression and how distinct enhancers controlling the same gene can have opposing effects on disease outcomes through cell type-selective activity.

scholarly journals Regulation of Th1 T Cell Differentiation by Iron via Upregulation of T Cell Immunoglobulin and Mucin Containing Protein-3 (TIM-3)

2021 ◽  
Vol 12 ◽  
Author(s):  
Christa Pfeifhofer-Obermair ◽  
Piotr Tymoszuk ◽  
Manfred Nairz ◽  
Andrea Schroll ◽  
Gloria Klais ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Iron Supplementation ◽  
Immune Cell ◽  
Cell Subset ◽  
Essential Element ◽  
T Cell Differentiation ◽  
Intracellular Pathogens ◽  
Iron Loading

Iron plays an important role in host–pathogen interactions, in being an essential element for both pathogen and host metabolism, but also by impacting immune cell differentiation and anti-microbial effector pathways. Iron has been implicated to affect the differentiation of T lymphocytes during inflammation, however, so far the underlying mechanism remained elusive. In order to study the role of iron in T cell differentiation we here investigated how dietary iron supplementation affects T cell function and outcome in a model of chronic infection with the intracellular bacterium Salmonella enterica serovar typhimurium (S. Typhimurium). Iron loading prior to infection fostered bacterial burden and, unexpectedly, reduced differentiation of CD4+ T helper cells type 1 (Th1) and expression of interferon-gamma (IFNγ), a key cytokine to control infections with intracellular pathogens. This effect could be traced back to iron-mediated induction of the negative immune checkpoint regulator T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), expressed on the surface of this T cell subset. In vitro experiments demonstrated that iron supplementation specifically upregulated mRNA and protein expression of TIM-3 in naïve Th cells in a dose-depdendent manner and hindered priming of those T cells towards Th1 differentiation. Importantly, administration of TIM-3 blocking antibodies to iron-loaded mice infected with S. Typhimurium virtually restored Th1 cell differentiation and significantly improved bacterial control. Our data uncover a novel mechanism by which iron modulates CD4+ cell differentiation and functionality and hence impacts infection control with intracellular pathogens. Specifically, iron inhibits the differentiation of naive CD4+ T cells to protective IFNγ producing Th1 lymphocytes via stimulation of TIM-3 expression. Finally, TIM-3 may serve as a novel drug target for the treatment of chronic infections with intracellular pathogens, specifically in iron loading diseases.

scholarly journals Leukocyte Localization in a Model of Innate Immune-Driven Colitis

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Jordan R. Jones ◽  
Anne-Marie C. Overstreet ◽  
Antonia M. Boger-May ◽  
David L. Boone
Keyword(s):  
Immune Cell ◽  
Cell Subset ◽  
Innate Immune ◽  
Lymphoid Cells ◽  
T Helper Cell ◽  
Cell Surface Markers ◽  
T Helper ◽  
Immune Cell Subset ◽  
Inflammatory State ◽  
Inflammatory Bowel

Background and Hypothesis:  Inflammatory bowel disease (IBD) is a disabling, chronic gut disorder involving immune dysregulation. Our lab has generated a murine IBD model in which the innate immune system drives inflammation. Innate lymphoid cells (ILCs), an innate immune cell subset that was recently discovered, exhibit many T-helper cell characteristics. ILCs, though few, produce cytokines, thereby significantly impacting tissue through local action in mucosal sites. They express the cell surface markers, CD90, which is unique to ILCs, and CD45, which all leukocyte types express. Colitis prevention in our model via ILC depletion indicates a role for ILCs in IBD. Therefore, we aimed to identify the ILCs’ localization in our murine model. We hypothesized that the ILCs will localize to inflamed areas of the intestinal lamina propria and into the intraepithelial spaces.  Experimental Design or Project Methods:  Mice expressing TNFAIP3, an inhibitor of NF-kB, were mated with adaptive immunity-lacking mice (RAG1-/-). RAG1-/- x Villin-TNFAIP3 (TRAG) mice had colitis that was 100% penetrant by age 6 weeks. Distal colons excised at age 4 weeks and 8 weeks were used for identifying CD45+ and CD90+ cells in both RAG and TRAG mice intestines via immunofluorescence.  Results:  We observed differences in the distributions of CD90+ and CD45+ cells within TRAG and RAG mice intestines.  Conclusion and Potential Impact:  Differences exist in intestinal leukocyte distributions within our models. Altered ILC distribution might reflect an inflammatory state or contribute to IBD pathology. This work may further elucidate ILCs’ role in IBD and as IBD treatment targets.

scholarly journals Immune Trait Shifts in Association With Tobacco Smoking: A Study in Healthy Women

2021 ◽  
Vol 12 ◽  
Author(s):  
Giulia Piaggeschi ◽  
Simona Rolla ◽  
Niccolò Rossi ◽  
Davide Brusa ◽  
Alessio Naccarati ◽  
...  
Keyword(s):  
T Cells ◽  
Tobacco Smoking ◽  
Immune Cell ◽  
Memory T Cells ◽  
Smoking Status ◽  
Cell Subset ◽  
Activation Marker ◽  
Healthy Women ◽  
Immune Traits ◽  
Cd8 Memory T Cells

Tobacco smoking is known to impact circulating levels of major immune cells populations, but its effect on specific immune cell subsets remains poorly understood. Here, using high-resolution data from 223 healthy women (25 current and 198 never smokers), we investigated the association between smoking status and 35,651 immune traits capturing immune cell subset frequencies. Our results confirmed that active tobacco smoking is associated with increased frequencies of circulating CD8+ T cells expressing the CD25 activation marker. Moreover, we identified novel associations between smoking status and relative abundances of CD8+ CD25+ memory T cells, CD8+ memory T cells expressing the CCR4 chemokine receptor, and CD4+CD8+ (double-positive) CD25+ T cells. We also observed, in current smokers, a decrease in the relative frequencies of CD4+ T cells expressing the CD38 activation marker and an increase in class-switched memory B cell isotypes IgA, IgG, and IgE. Finally, using data from 135 former female smokers, we showed that the relative frequencies of immune traits associated with active smoking are usually completely restored after smoking cessation, with the exception of subsets of CD8+ and CD8+ memory T cells, which persist partially altered. Our results are consistent with previous findings and provide further evidence on how tobacco smoking shapes leukocyte cell subsets proportion toward chronic inflammation.

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