scholarly journals Coevolution of TH1, TH2, and TH17 Responses during Repeated Pulmonary Exposure toAspergillus fumigatusConidia

2010 ◽  
Vol 79 (1) ◽  
pp. 125-135 ◽  
Author(s):  
Benjamin J. Murdock ◽  
Andrew B. Shreiner ◽  
Roderick A. McDonald ◽  
John J. Osterholzer ◽  
Eric S. White ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Allergic Bronchopulmonary Aspergillosis ◽  
Myeloid Cell ◽  
Hyphal Growth ◽  
Cell Polarization ◽  
Repeated Exposure ◽  
Invasive Infection ◽  
Pulmonary Exposure

ABSTRACTAspergillus fumigatus, a ubiquitous airborne fungus, can cause invasive infection in immunocompromised individuals but also triggers allergic bronchopulmonary aspergillosis in a subset of otherwise healthy individuals repeatedly exposed to the organism. This study addresses a critical gap in our understanding of the immunoregulation in response to repeated exposure toA. fumigatusconidia. C57BL/6 mice were challenged intranasally withA. fumigatusconidia weekly, and leukocyte composition, activation, and cytokine production were examined after two, four, and eight challenges. Approximately 99% ofA. fumigatusconidia were cleared within 24 h after inoculation, and repeated exposure toA. fumigatusconidia did not result in hyphal growth or accumulation of conidia with time. After 2 challenges, there was an early influx of neutrophils and regulatory T (Treg) cells into the lungs but minimal inflammation. Repeated exposure promoted sustained expansion of the draining lymph nodes, while the influx of eosinophils and other myeloid cells into the lungs peaked after four exposures and then decreased despite continuedA. fumigatuschallenges. Goblet cell metaplasia and low-level fibrosis were evident during the response. Repeated exposure toA. fumigatusconidia induced T cell activation in the lungs and the codevelopment by four exposures of TH1, TH2, and TH17 responses in the lungs, which were maintained through eight exposures. Changes in CD4 T cell polarization or Tregnumbers did not account for the reduction in myeloid cell numbers later in the response, suggesting a non-T-cell regulatory pathway involved in dampening inflammation during repeated exposure toA. fumigatusconidia.

IMMU-04. UNVEILING THE TUMOR-METABOLOME-IMMUNITY AXIS OF GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi92-vi92
Author(s):  
Mirco Friedrich ◽  
Lukas Bunse ◽  
Roman Sankowski ◽  
Wolfgang Wick ◽  
Marco Prinz ◽  
...  
Keyword(s):  
T Cell ◽  
Single Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Myeloid Cell ◽  
Tumor Evolution ◽  
Large Neutral Amino Acid ◽  
Immune Microenvironment ◽  
Idh Mutations

Abstract The glioma microenvironment orchestrates tumor evolution, progression, and resistance to therapy. In high-grade gliomas, microglia and monocyte-derived macrophages constitute up to 70% of the tumor mass. However, the dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and demonstrate their strict control by the tumor genotype. We report the unexpected and clinically highly relevant finding that human as well as murine gliomas with Isocitrate Dehydrogenase (IDH)1-R132H, a key oncogenic driver mutation of glioma, subdue their innate immune microenvironment by prompting a multifaceted reprogramming of myeloid and T cell metabolism. We employed integrated single-cell transcriptomic, time-of-flight mass cytometry and proteomic analyses of human healthy cortex control and glioma samples to identify myeloid cell subsets with distinct fates in IDH-mutated glioma that diverge from canonical trajectories of antigen-presenting cells as a result of a monocyte-to-macrophage differentiation block. Moving beyond single time point assessments, we now longitudinally describe differential immune cell infiltration and phenotype dynamics during glioma progression that are orchestrated by a fluctuating network of resident microglial cells and educated recruited immune cells. IDH mutations in glioma induce a tolerogenic alignment of their immune microenvironment through increased tryptophan uptake via large neutral amino acid transporter (LAT1)-CD98 and subsequent activation of the aryl hydrocarbon receptor (AHR) in educated blood-borne macrophages. In experimental tumor models, this immunosuppressive phenotype was reverted by LAT1-CD98 and AHR inhibitors. Taken together with direct effects on T cell activation, our findings not only link this oncogenic metabolic pathway to distinct immunosuppressive pathways but also provide the rationale and novel molecular targets for the development of immunotherapeutic concepts addressing the disease-defining microenvironmental effects of IDH mutations.

Opposing effect of mesenchymal stem cells on Th1 and Th17 cell polarization according to the state of CD4+ T cell activation

2011 ◽  
Vol 135 (1-2) ◽  
pp. 10-16 ◽  
Author(s):  
Flavio Carrión ◽  
Estefania Nova ◽  
Patricia Luz ◽  
Felipe Apablaza ◽  
Fernando Figueroa
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Th17 Cell ◽  
Cell Activation ◽  
Cell Polarization ◽  
The State ◽  
Cd4 T Cell ◽  
Opposing Effect

scholarly journals Engagement of SLAMF3 enhances CD4+ T-cell sensitivity to IL-2 and favors regulatory T-cell polarization in systemic lupus erythematosus

2016 ◽  
Vol 113 (33) ◽  
pp. 9321-9326 ◽  
Author(s):  
Denis Comte ◽  
Maria P. Karampetsou ◽  
Katalin Kis-Toth ◽  
Nobuya Yoshida ◽  
Sean J. Bradley ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Lupus Erythematosus ◽  
Regulatory T Cell ◽  
Cell Activation ◽  
Cell Polarization ◽  
Systemic Lupus ◽  
Signaling Lymphocytic Activation Molecule

Signaling lymphocytic activation molecule family 3 (SLAMF3/Ly9) is a coregulatory molecule implicated in T-cell activation and differentiation. Systemic lupus erythematosus (SLE) is characterized by aberrant T-cell activation and compromised IL-2 production, leading to abnormal regulatory T-cell (Treg) development/function. Here we show that SLAMF3 functions as a costimulator on CD4+ T cells and influences IL-2 response and T helper cell differentiation. SLAMF3 ligation promotes T-cell responses to IL-2 via up-regulation of CD25 in a small mothers against decapentaplegic homolog 3 (Smad3)-dependent mechanism. This augments the activation of the IL-2/IL-2R/STAT5 pathway and enhances cell proliferation in response to exogenous IL-2. SLAMF3 costimulation promotes Treg differentiation from naïve CD4+ T cells. Ligation of SLAMF3 receptors on SLE CD4+ T cells restores IL-2 responses to levels comparable to those seen in healthy controls and promotes functional Treg generation. Taken together, our results suggest that SLAMF3 acts as potential therapeutic target in SLE patients by augmenting sensitivity to IL-2.

scholarly journals Antibodies to ILT3 abrogate myeloid immunosuppression and enable tumor killing

2021 ◽  
Author(s):  
Philip E Brandish ◽  
Anthony Palmieri ◽  
Gulesi Ayanoglu ◽  
Jeanne Baker ◽  
Raphael Bueno ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Cell Activation ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Soluble Form ◽  
Myeloid Suppressor Cells ◽  
Wide Range ◽  
Tumor Killing

Tumor myeloid suppressor cells impede response to T cell checkpoint immunotherapy. Immunoglobulin-like transcript 3 (ILT3, gene name, LILRB4) expressed on dendritic cells (DCs) promotes antigen-specific tolerance. Circulating monocytic MDSCs that express ILT3 have been linked to clinical outcomes and a soluble form of ILT3 is elevated in certain cancers. We find that LILRB4 expression is correlated with Gene Expression Profile of T-cell inflamed tumor microenvironment shown to be significantly associated with response to the anti-PD1 antibody pembrolizumab across several tumor types. A potent and selective anti-ILT3 mAb effectively antagonized IL-10 polarization of DCs and enabled T cell priming. In an MLR assay anti-ILT3 combined with pembrolizumab afforded greater CD8+ T cell activation compared to either agent alone. Anti-ILT3 antibodies impaired the acquisition of a suppressive phenotype of monocytes co-cultured with SK-MEL-5 cancer cells, accompanied by a reduction in surface detection of peptidase inhibitor 16, a cis interaction candidate for ILT3. Growth of myeloid cell-abundant SK-MEL-5 tumors was abrogated by ILT3 blockade and remodeling of the immune tumor microenvironment was evident by CyTOF. These data support the testing of anti-ILT3 antibodies for the treatment of a wide range of solid tumors replete with myeloid cells.

scholarly journals 798 CDX-585, A bispecific antibody with dual targeting of ILT4 and PD-1 checkpoint pathways

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A833-A833
Author(s):  
Laura Vitale ◽  
Michael Murphy ◽  
Collin Xia ◽  
Zeyu Peng ◽  
Thomas O'Neill ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Clinical Chemistry ◽  
Primary Cultures ◽  
Resistance Mechanism ◽  
Myeloid Cell ◽  
Receptor Activation ◽  
Pilot Studies ◽  
Enhanced Production

BackgroundActivation of the ITIM-bearing ILT4/LILRB2 receptor by its cognate ligands (HLA-G and HLA Class I) has been postulated as a resistance mechanism for checkpoint blockade of PD-1 and CTLA-4. Dual inhibition of receptors that suppress myeloid and T cell compartments through the generation of bispecific antibodies (bsAbs) is a promising strategy to improve outcomes for patients whose tumors are resistant to checkpoint inhibition.MethodsWe describe the discovery and characterization of CDX-585 a bsAb developed from novel ILT4 and PD-1 antagonist mAbs that revert myeloid cell suppression by antagonizing ILT4 and activating T-cell responses through PD-1 inhibition. The bsAb was engineered as a tetravalent molecule using the PD-1 IgG1 mAb linked to scFv of the ILT4 mAb at the C-terminus of the heavy chain. A series of mutations were introduced in the Fc domain to eliminate Fcy receptor binding and increase affinity to the neonatal Fc receptor. CDX-585 has good biophysical characteristics and retains functional properties similar to, or better, than the parental mAbs.ResultsCDX-585 has sub-nanomolar affinity binding to ILT4 and PD-1 and is a potent competitor of their respective ligands. Primary cultures of human macrophages and dendritic cells treated with CDX-585 enhanced production of inflammatory cytokines/chemokines, which was further potentiated in the presence of toll like receptor activation with lipopolysaccharide (LPS). CDX-585 was particularly effective in promoting T cell activation as measured by mixed lymphocyte reactions, and in polarizing macrophages towards M1 based on their cytokine profile. Pilot studies in mice and cynomolgus macaques confirmed a favorable pharmacokinetic profile without adverse effects of treatment noted in clinical observations or clinical chemistry.ConclusionsCDX-585 effectively combines ILT4 and PD-1 blockade into one molecule with favorable biophysical and functional characteristics supporting the initiation of development activities including manufacturing and IND-enabling studies.

scholarly journals The second touch hypothesis: T cell activation, homing and polarization

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 37 ◽  
Author(s):  
Klaus Ley
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antigen Presenting Cells ◽  
Cell Interaction ◽  
Cell Polarization ◽  
Antigen Presenting ◽  
Inflamed Tissue

The second touch hypothesis states that T cell activation, proliferation, induction of homing receptors and polarization are distinguishable and, at least in part, sequential. The second touch hypothesis maintains that full T cell polarization requires T cell interaction with antigen-presenting cells (DCs, macrophages, B cells and certain activated stromal cells) in the non-lymphoid tissue where the antigen resides. Upon initial antigen encounter in peripheral lymph nodes (PLN), T cells become activated, proliferate and express homing receptors that enable them to recirculate to the (inflamed) tissue that contains the antigen. Differentiation into the T helper lineages Th1, Th2, Th17 and induced regulatory T cells (iTreg) requires additional antigen presentation by tissue macrophages and other antigen presenting cells (APCs) in the inflamed tissue. Here, I present a conceptual framework for the importance of peripheral (non-lymphoid) antigen presentation to antigen-experienced T cells.

scholarly journals Inhibition of T Cells Provides Protection against Early Invasive Pneumococcal Disease

2010 ◽  
Vol 78 (12) ◽  
pp. 5287-5294 ◽  
Author(s):  
Kim LeMessurier ◽  
Hans Häcker ◽  
Elaine Tuomanen ◽  
Vanessa Redecke
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Invasive Pneumococcal Disease ◽  
T Cell Activation ◽  
Pneumococcal Disease ◽  
Cell Activation ◽  
Class Ii ◽  
Invasive Infection ◽  
Deficient Mice

ABSTRACT Infections caused by Streptococcus pneumoniae are major causes of morbidity and mortality, which are in part mediated by immune cell-dependent mechanisms. Yet, the specific contributions of individual cell types to immunopathology are only partially understood. T cells are well characterized with respect to their function in protective humoral immune responses; however, their roles during early stages of infection and invasive pneumococcal disease (IPD) are less well defined. Using a mouse model of pneumococcal sepsis, we found that CD4+ T cells were recruited to the lung as early as 12 h after intranasal infection. Recruitment was accompanied by upregulation of CD69 and B7-H1, reflecting T-cell activation. Unexpectedly, major histocompatibility complex (MHC) class II-deficient mice, which lack CD4+ T cells, displayed an increased survival despite comparable bacterial titers in the blood, spleen, and lung. The higher survival correlated with a lower cytokine and chemokine response upon S. pneumoniae challenge in MHC class II-deficient mice, suggesting that inflammation may contribute to the mortality of IPD. Comparable to the case for MHC class II-deficient mice, antibody-mediated depletion of CD4+ T cells and drug-induced inhibition of T-cell function with cyclosporine, or interference with T-cell activation using CTLA4-immunoglobulin (Abatacept), led to significant increases in survival during IPD. Our results reveal an important and adverse role of CD4+ T cells in the pathogenesis of IPD and suggest that modulation of T-cell activation during early phases of S. pneumoniae invasive infection may provide a therapeutic option.

scholarly journals IMMU-34. LANDSCAPE OF GLIOBLASTOMA-ASSOCIATED IMMUNITY BY INTEGRATION OF scRNA-SEQ AND SPATIAL TRANSCRIPTOMICS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii112-ii112
Author(s):  
Vidhya Ravi ◽  
Nicolas Neidert ◽  
Kevin Joseph ◽  
Juergen Beck ◽  
Oliver Schnell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Lymphoid Cells ◽  
T Cell Exhaustion ◽  
Cellular Interactions ◽  
Cell Exhaustion

Abstract The diversity of molecular states and cellular plasticity of immune cells within the glioblastoma (GBM) environment remain poorly investigated. Here, we conduct deep transcriptional profiling of lymphoid and myeloid cell populations by scRNA-sequencing, map potential cellular interactions and cytokine responses that lead to the dysfunctional and exhausted phenotype of T cells. We identified Interleukin 10 (IL-10) response during T cell activation, which lead to a dysfunctional state of T cells. By the use of a novel method: The nearest functionally connected neighbor (NFCN), an in-silico model to explore cell-cell interaction, the dysfunctional/exhausted phenotype was found to be driven by subset of myeloid cells defined by high expression of HMOX1. By using spatial transcriptomic RNA-sequencing, we identified a correlation between T cell exhaustion and colocalized mesenchymal gene expression. We found that HMOX1 expressing myeloid cells occupying regions marked by T cell exhaustion. Using a human neocortical slice model with myeloid cell depletion we confirmed the functional interaction of myeloid and lymphoid cell leading to the dysfunctional state of T cells. A comprehensive understanding of cellular states and plasticity of lymphoid cells in GBM aids in providing successful immunotherapeutic approaches.

scholarly journals The second touch hypothesis: T cell activation, homing and polarization

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 37 ◽  
Author(s):  
Klaus Ley
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antigen Presenting Cells ◽  
Cell Interaction ◽  
Cell Polarization ◽  
Antigen Presenting ◽  
Inflamed Tissue

The second touch hypothesis states that T cell activation, proliferation, induction of homing receptors and polarization are distinguishable and, at least in part, sequential. The second touch hypothesis maintains that full T cell polarization requires T cell interaction with antigen-presenting cells (DCs, macrophages, B cells and certain activated stromal cells) in the non-lymphoid tissue where the antigen resides. Upon initial antigen encounter in peripheral lymph nodes (PLN), T cells become activated, proliferate and express homing receptors that enable them to recirculate to the (inflamed) tissue that contains the antigen. Differentiation into the T helper lineages Th1, Th2, Th17 and induced regulatory T cells (iTreg) requires additional antigen presentation by tissue macrophages and other antigen presenting cells (APCs) in the inflamed tissue. Here, I present a conceptual framework for the importance of peripheral (non-lymphoid) antigen presentation to antigen-experienced T cells.

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