IMMU-17. SYSTEMIC IMMUNOSUPPRESSION OF CD4+ T HELPER CELLS IN GLIOMA

Abstract Cancer is a systemic disease. Due to the exceedingly rare occurrence of metastasis of cerebral glioma, systemic alterations have, however, not been considered to play a major role in disease progression of glioma. CD4+ T helper (TH) cells orchestrate the adaptive immune response in an antigen-specific, cytokine mediated manner. The aim of our study was to investigate how far cerebral glioma impacts the systemic CD4+ immune repertoire. We therefore analyzed the peripheral blood CD4+ TH cell phenotype and cytokine production in 100 patients with IDHwt, 30 IDHmut and 16 IDHmut 1p19q co-deleted gliomas in comparison with age-matched healthy donors (HD). We found a significant skewing of the peripheral phenotype in IDHwt glioma patients, showing a TH1 expansion and reduced numbers of T follicular helper cells (TFH), TH1* and mucosa associated invariant T (MAIT) cells, while TH2 and TH17 percentages remained stable compared to IDHmut and HD. Interestingly, although TH1 cells were dominant in IDHwt patients, intracellular cytokine staining showed a distinct reduction of IFNg and TNFa production after in vitro stimulation, while IL-4 was significantly increased compared to HD. No alterations between all groups were observed in IL-2, IL-10 or IL-17 production. Profiling of metabolic surface markers further revealed three distinct groups of CD4+ T cells which are altered in IDHwt patients, indicating a metabolic shift in the CD4+ repertoire compared to HD. Taken together, our results show a CD4+ TH cell type specific skewing of the peripheral immune repertoire in patients with IDHwt gliomas. Our data highlights the importance of considering malignant glioma as a systemic disease that fundamentally alters the immune repertoire in affected patients.

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P16.03 Cerebral gliom alters the peripheral CD4+ T helper cell phenotype

Neuro-Oncology ◽

10.1093/neuonc/noab180.196 ◽

2021 ◽

Vol 23 (Supplement_2) ◽

pp. ii56-ii56

Author(s):

M Mohme ◽

C Maire ◽

A Rünger ◽

L Glau ◽

E Tolosa ◽

...

Keyword(s):

Systemic Disease ◽

Intracellular Cytokine Staining ◽

Adaptive Immune Response ◽

Cell Phenotype ◽

Cerebral Glioma ◽

T Helper ◽

Immune Repertoire ◽

Mait Cells ◽

Th Cell

Abstract BACKGROUND Cancer is a systemic disease. Due to the exceedingly rare occurrence of metastasis of cerebral glioma, systemic alterations have, however, not been considered to play a major role in disease progression of glioma. CD4+ T helper (TH) cells orchestrate the adaptive immune response in an antigen-specific, cytokine mediated manner. The aim of our study was to investigate how far cerebral glioma impacts the systemic CD4+ immune repertoire. MATERIAL AND METHODS We performed flow-cytometry analysis of the peripheral blood CD4+ TH cell phenotype and cytokine production in 100 patients with IDHwt, 30 IDHmut and 16 IDHmut 1p19q co-deleted gliomas in comparison with age-matched healthy donors (HD). Data was analyzed using a Fortessa LSR and Diva software. Multiparameter analyses were performed using UMAP and SpadeVizR trees. The study was approved by the ethics committee (PV4904). RESULTS We found a significant skewing of the peripheral immunophenotype in IDHwt glioma patients, showing a TH1 expansion and reduced numbers of T follicular helper cells (TFH), TH1* and mucosa associated invariant T (MAIT) cells (p<0.001), while TH2 and TH17 percentages remained stable compared to IDHmut and HD. Although TH1 cells were dominant in IDHwt patients (p<0.01), intracellular cytokine staining showed a reduction of IFNγ and TNFα production after in vitro stimulation, while IL-4 was significantly increased compared to HD (p<0.05). No alterations between all groups were observed in IL-2, IL-10 or IL-17 production. Profiling of metabolic surface markers further revealed increased expression of GLUT1 on CD4+ T cells in IDHwt patients, indicating an activated CD4+ repertoire compared to HD. CONCLUSION Taken together, our results show a CD4+ TH cell type specific skewing of the peripheral immune repertoire in patients with IDHwt gliomas. Our data highlights the importance of considering malignant glioma as a disease with profound systemic effects fundamentally altering the immune repertoire in affected patients.

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Type I Interferons promote maintenance and function of follicular T helper cells in vitro

10.1055/s-0038-1677255 ◽

2019 ◽

Author(s):

S Ehrlich ◽

K Wild ◽

M Smits ◽

K Zoldan ◽

M Hofmann ◽

...

Keyword(s):

T Helper Cells ◽

Type I Interferons ◽

Type I ◽

T Helper ◽

Helper Cells ◽

Follicular T Helper Cells ◽

And Function

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Generation of IL-8 and IL-9 Producing CD4+T Cells Is Affected by Th17 Polarizing Conditions and AHR Ligands

Mediators of Inflammation ◽

10.1155/2014/182549 ◽

2014 ◽

Vol 2014 ◽

pp. 1-14 ◽

Cited By ~ 13

Author(s):

Michaela Gasch ◽

Tina Goroll ◽

Mario Bauer ◽

Denise Hinz ◽

Nicole Schütze ◽

...

Keyword(s):

T Cells ◽

T Helper Cells ◽

Th17 Cells ◽

Immune Cell ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Helper Cells ◽

Aryl Hydrocarbon

The T helper cell subsets Th1, Th2, Th17, and Treg play an important role in immune cell homeostasis, in host defense, and in immunological disorders. Recently, much attention has been paid to Th17 cells which seem to play an important role in the early phase of the adoptive immune response and autoimmune disease. When generating Th17 cells underin vitroconditions the amount of IL-17A producing cells hardly exceeds 20% while the nature of the remaining T cells is poorly characterized. As engagement of the aryl hydrocarbon receptor (AHR) has also been postulated to modulate the differentiation of T helper cells into Th17 cells with regard to the IL-17A expression we ask how far do Th17 polarizing conditions in combination with ligand induced AHR activation have an effect on the production of other T helper cell cytokines. We found that a high proportion of T helper cells cultured under Th17 polarizing conditions are IL-8 and IL-9 single producing cells and that AHR activation results in an upregulation of IL-8 and a downregulation of IL-9 production. Thus, we have identified IL-8 and IL-9 producing T helper cells which are subject to regulation by the engagement of the AHR.

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Immunogenicity risk assessment for biotherapeutics through in vitro detection of CD134 and CD137 on T helper cells

mAbs ◽

10.1080/19420862.2021.1898831 ◽

2021 ◽

Vol 13 (1) ◽

pp. 1898831

Author(s):

Sivan Cohen ◽

Srividya Myneni ◽

Anna Batt ◽

Joyce Guerrero ◽

Jochen Brumm ◽

...

Keyword(s):

Risk Assessment ◽

T Helper Cells ◽

T Helper ◽

Helper Cells

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A Signal Transducer and Activator of Transcription (Stat)4-independent Pathway for the Development of T Helper Type 1 Cells

Journal of Experimental Medicine ◽

10.1084/jem.188.6.1191 ◽

1998 ◽

Vol 188 (6) ◽

pp. 1191-1196 ◽

Cited By ~ 127

Author(s):

Mark H. Kaplan ◽

Andrea L. Wurster ◽

Michael J. Grusby

Keyword(s):

Delayed Type Hypersensitivity ◽

Th2 Cells ◽

Signal Transducer ◽

T Helper ◽

Th1 Cell ◽

Th Cells ◽

Th Cell ◽

Ifn Γ

The differentiation of T helper (Th) cells is regulated by members of the signal transducer and activator of transcription (STAT) family of signaling molecules. We have generated mice lacking both Stat4 and Stat6 to examine the ability of Th cells to develop in the absence of these two transcription factors. Stat4, Stat6−/− lymphocytes fail to differentiate into interleukin (IL)-4–secreting Th2 cells. However, in contrast to Stat4−/− lymphocytes, T cells from Stat4, Stat6−/− mice produce significant amounts of interferon (IFN)-γ when activated in vitro. Although Stat4, Stat6−/− lymphocytes produce less IFN-γ than IL-12–stimulated control lymphocytes, equivalent numbers of IFN-γ–secreting cells can be generated from cultures of Stat4, Stat6−/− lymphocytes activated under neutral conditions and control lymphocytes activated under Th1 cell–promoting conditions. Moreover, Stat4, Stat6−/− mice are able to mount an in vivo Th1 cell–mediated delayed-type hypersensitivity response. These results support a model of Th cell differentiation in which the generation of Th2 cells requires Stat6, whereas a Stat4-independent pathway exists for the development of Th1 cells.

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T helper cell polarisation as a measure of the maturation of the immune response

Mediators of Inflammation ◽

10.1080/0929350310001619744 ◽

2003 ◽

Vol 12 (5) ◽

pp. 285-292 ◽

Cited By ~ 4

Author(s):

Scott B. Cameron ◽

Ellen H. Stolte ◽

Anthony W. Chow ◽

Huub F. J. Savelkoul

Keyword(s):

Immune Response ◽

T Cells ◽

Intracellular Cytokine Staining ◽

T Helper Cell ◽

Helper Cell ◽

Enzyme Linked Immunosorbent Assay ◽

Intracellular Cytokine ◽

T Helper

Background:T helper cell polarisation is important under chronic immune stimulatory conditions and drives the type of the evolving immune response. Mice treated with superantigensin vivodisplay strong effects on Thsubset differentiation. The aim of the study was to detect the intrinsic capacity of T cells to polarise under variousex vivoconditions.Methods:Purified CD4+T cells obtained from superantigen-treated mice were cultured under Thpolarising conditionsin vitro. By combining intracellular cytokine staining and subsequent flow cytometric analysis with quantitative cytokine measurements in culture supernatants by enzyme-linked immunosorbent assay (ELISA), the differential Thpolarising capacity of the treatment can be detected in a qualitative and quantitative manner.Results and conclusions:BALB/c mice were shown to be biased to develop strong Th2 polarised immune responses using Th0 stimulation of purified CD4+T cells from phosphate-buffered saline-treated mice. Nevertheless, our analysis methodology convincingly showed that even in these mice, Toxic Shock Syndrome Toxin-1 treatmentin vivoresulted in a significantly stronger Th1 polarising effect than control treatment. Our results indicate that populations of Thcells can be assessed individually for their differential Th1 or Th2 maturation capacityin vivoby analysing robustin vitropolarisation cultures combined with intracellular cytokine staining and ELISA.

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KS01.3.A Tumoral MHC class II expression in gliomas drives T cell exhaustion

Neuro-Oncology ◽

10.1093/neuonc/noab180.007 ◽

2021 ◽

Vol 23 (Supplement_2) ◽

pp. ii3-ii3

Author(s):

Y Chih ◽

K Sahm ◽

A Sadik ◽

T Bunse ◽

N Trautwein ◽

...

Keyword(s):

T Cell ◽

Cell Line ◽

T Helper Cells ◽

Glioma Cell Line ◽

Human Glioma ◽

T Helper ◽

Transcriptomic Data ◽

Helper Cells ◽

Mhcii Expression

Abstract BACKGROUND Neoepitopes are presented on major histocompatibility class II (MHCII) molecules. In glioma, for instance, the recurrent driver mutation IDH1R132H was shown to bear an MHCII-restricted epitope in preclinical and clinical vaccine studies. The general relevance of MHCII expression in glioma for antitumor immunity, however, remains unknown. Here we evaluate stromal and tumoral MHCII expression, functionality, and its association with survival in gliomas. MATERIAL AND METHODS Immunostaining of human glioma tissues was used to identify tumoral, endothelial, and microglial MHCII expression and to enumerate T cell infiltrates. To gain insights into tumoral MHCII expression, bulk transcriptomic data from TCGA and single-cell transcriptomic data from publicly available datasets were analyzed. MHC ligandome analyses of an MHCII+ glioma cell line and human glioma tissues were used to determine the functionality of MHCII in vitro and ex vivo. Functional in vitro co-culture assays with an HLA-DR-matched tetanus toxoid (TT) epitope-overexpressing glioma cell line and in vitro-expanded TT-reactive T cells from healthy donors were used to examine direct target recognition by T helper cells. CRISPR-Cas9-mediated knockout of MHCII in preclinical hypermutant glioblastoma cell line GL261 was employed to further validate the consequences of tumoral MHCII expression and to probe potential clinical intervention with existing therapies. RESULTS MHCII is expressed in the majority of gliomas and associated with increased infiltration of T cells. In 10% of the analyzed glioma tissues and a subset of single cells, tumoral MHCII expression is detected. Clinical and transcriptomic data reveal that tumoral MHCII is associated with poor prognosis, cytokine responses, immune inhibition and T cell differentiation. Ligandome analyses evidence presentation of peptides by MHCII molecules on glioma cells. In in vitro assays, TT-reactive T helper cells specifically produce IFNg when co-cultured with MHCII+ glioma cells upon the presence of co-stimulation. In agreement with the clinical data, preclinical murine models demonstrate that tumoral MHCII expression leads to reduced survival. Co-culture assay shows that tumoral MHCII results in upregulation of PD-1 on T helper cells antigen-specifically. Concordantly, immune checkpoint blockade (ICB) therapy slows the disease progression of mice carrying MHCII+ tumors. CONCLUSION MHCII is expressed in gliomas by a subset of tumor cells. Although tumoral MHCII is functional, it is associated with poor survival in both clinical data and preclinical models. T cell exhaustion induced by tumoral MHCII expression can, in part, be overcome by ICB in vivo. Further experiments are required to decipher tumor cell intrinsic and microenvironmental consequences of tumoral MHCII expression.

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Investigation of Cytotoxic T Lymphocyte Function during Allorejection in the Anterior Chamber of the Eye

International Journal of Molecular Sciences ◽

10.3390/ijms21134660 ◽

2020 ◽

Vol 21 (13) ◽

pp. 4660

Author(s):

Hsin-Fang Chang ◽

Marie-Louise Wirkner ◽

Elmar Krause ◽

Jens Rettig

Keyword(s):

Immune Responses ◽

Anterior Chamber ◽

T Helper Cells ◽

Cytotoxic T Lymphocyte ◽

Diabetes Research ◽

Lymphocyte Function ◽

T Helper ◽

Helper Cells

Cytotoxic T lymphocytes (CTL) are an essential part of our immune system by killing infected and malignant cells. To fully understand this process, it is necessary to study CTL function in the physiological setting of a living organism to account for their interplay with other immune cells like CD4+ T helper cells and macrophages. The anterior chamber of the eye (ACE), originally developed for diabetes research, is ideally suited for non-invasive and longitudinal in vivo imaging. We take advantage of the ACE window to observe immune responses, particularly allorejection of islets of Langerhans cells by CTLs. We follow the onset of the rejection after vascularization on islets until the end of the rejection process for about a month by repetitive two-photon microscopy. We find that CTLs show reduced migration on allogeneic islets in vivo compared to in vitro data, indicating CTL activation. Interestingly, the temporal infiltration pattern of T cells during rejection is precisely regulated, showing enrichment of CD4+ T helper cells on the islets before arrival of CD8+ CTLs. The adaptation of the ACE to immune responses enables the examination of the mechanism and regulation of CTL-mediated killing in vivo and to further investigate the killing in gene-deficient mice that resemble severe human immune diseases.

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