scholarly journals Mice from a genetically resistant background lacking the interferon γ receptor are susceptible to infection with Leishmania major but mount a polarized T helper cell 1-type CD4+ T cell response.

1995 ◽  
Vol 181 (3) ◽  
pp. 961-971 ◽  
Author(s):  
K Swihart ◽  
U Fruth ◽  
N Messmer ◽  
K Hug ◽  
R Behin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Leishmania Major ◽  
T Helper Cell ◽  
Cd4 T Cell ◽  
Helper Cell ◽  
Wild Type ◽  
T Helper ◽  
Ifn Gamma ◽  
Gamma Receptor

Mice with homologous disruption of the gene coding for the ligand-binding chain of the interferon (IFN) gamma receptor and derived from a strain genetically resistant to infection with Leishmania major have been used to study further the role of this cytokine in the differentiation of functional CD4+ T cell subsets in vivo and resistance to infection. Wild-type 129/Sv/Ev mice are resistant to infection with this parasite, developing only small lesions, which resolve spontaneously within 6 wk. In contrast, mice lacking the IFN-gamma receptor develop large, progressing lesions. After infection, lymph nodes (LN) and spleens from both wild-type and knockout mice showed an expansion of CD4+ cells producing IFN-gamma as revealed by measuring IFN-gamma in supernatants of specifically stimulated CD4+ T cells, by enumerating IFN-gamma-producing T cells, and by Northern blot analysis of IFN-gamma transcripts. No biologically active interleukin (IL) 4 was detected in supernatants of in vitro-stimulated LN or spleen cells from infected wild-type or deficient mice. Reverse transcription polymerase chain reaction analysis with primers specific for IL-4 showed similar IL-4 message levels in LN from both types of mice. The IL-4 message levels observed were comparable to those found in similarly infected C57BL/6 mice and significantly lower than the levels found in BALB/c mice. Anti-IFN-gamma treatment of both types of mice failed to alter the pattern of cytokines produced after infection. These data show that even in the absence of IFN-gamma receptors, T helper cell (Th) 1-type responses still develop in genetically resistant mice with no evidence for the expansion of Th2 cells.

scholarly journals Regulation of T Cell Responses by Ionic Salt Signals

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2365
Author(s):  
Christina E. Zielinski
Keyword(s):  
T Cells ◽  
T Cell ◽  
Sodium Chloride ◽  
T Cell Responses ◽  
T Helper Cell ◽  
Helper Cell ◽  
T Helper ◽  
Tissue Microenvironment ◽  
Cell Responses ◽  
The Impact

T helper cell responses are tailored to their respective antigens and adapted to their specific tissue microenvironment. While a great proportion of T cells acquire a resident identity, a significant proportion of T cells continue circulating, thus encountering changing microenvironmental signals during immune surveillance. One signal, which has previously been largely overlooked, is sodium chloride. It has been proposed to have potent effects on T cell responses in the context of autoimmune, allergic and infectious tissue inflammation in mouse models and humans. Sodium chloride is stringently regulated in the blood by the kidneys but displays differential deposition patterns in peripheral tissues. Sodium chloride accumulation might furthermore be regulated by dietary intake and thus by intentional behavior. Together, these results make sodium chloride an interesting but still controversial signal for immune modulation. Its downstream cellular activities represent a potential therapeutic target given its effects on T cell cytokine production. In this review article, we provide an overview and critical evaluation of the impact of this ionic signal on T helper cell polarization and T helper cell effector functions. In addition, the impact of sodium chloride from the tissue microenvironment is assessed for human health and disease and for its therapeutic potential.

Ligand-Induced Autoregulation of IFN-gamma Receptor beta Chain Expression in T Helper Cell Subsets

Science ◽  
1995 ◽  
Vol 270 (5239) ◽  
pp. 1215-1218 ◽  
Author(s):  
E. A. Bach ◽  
S. J. Szabo ◽  
A. S. Dighe ◽  
A. Ashkenazi ◽  
M. Aguet ◽  
...  
Keyword(s):  
T Helper Cell ◽  
Helper Cell ◽  
Beta Chain ◽  
T Helper ◽  
Ifn Gamma ◽  
Gamma Receptor ◽  
Receptor Beta

Defective T-helper cell function after T-cell–depleting therapy affecting naive and memory populations

Blood ◽  
2002 ◽  
Vol 99 (11) ◽  
pp. 4053-4062 ◽  
Author(s):  
Andreas Heitger ◽  
Patricia Winklehner ◽  
Petra Obexer ◽  
Johannes Eder ◽  
Claudia Zelle-Rieser ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Interleukin 2 ◽  
T Helper Cell ◽  
Helper Cell ◽  
High Dose ◽  
T Helper

Impaired T-cell function after T-cell– depleting (TCD) therapy has been hypothesized to be related to a transient predominance of extrathymically expanding memory T cells. To test whether after TCD therapy the naive T-helper cell population is functionally intact, the in vitro immune response of CD4+CD45RA+ (naive) and of CD4+CD45RA− (memory) cells to polyclonal mitogens (immobilized anti-CD3, phytohemagglutinin) was analyzed by flow cytometry in 22 pediatric patients after high-dose chemotherapy (including 5 after autologous and 5 after allogeneic stem cell support). At 1 to 3 months after TCD therapy, patient samples showing decreased lymphoproliferative responses also showed a reduced induction of the early activation marker CD69 by CD4+ T cells from 4 to 72 hours after stimulation even when supplemented with exogenous interleukin-2. This defect affected CD4+CD45RA− cells, but, strikingly, also CD4+CD45RA+ cells, including samples in which CD4+CD45RA+ cells were more than 90/μL, thus indicating ongoing thymopoiesis. Histogram analyses showed the median peak channel of CD69 in control CD4+CD45RA+cells rising 98-fold (median) but only 28-fold in patient cells (P < .0001). Apoptosis as detected by annexin V staining was increased in resting patient CD4+ T cells (25% versus 6%) and also affected CD4+CD45RA+ cells (12% versus 5%, P < .01). When peripheral blood mononuclear cells (PBMCs) were enriched for T cells, stimulatory responses of CD4+ cells and of CD4+CD45RA+ cells markedly improved. Thus, after TCD therapy suppressor factors contained in the non–T-cell fraction of PBMCs may affect T-helper cells irrespective of their naive or memory phenotype thus extending T-cell dysfunction to the presumably thymus-dependently regenerated T cells.

Age‐related alterations in human gut CD4 T cell phenotype, T helper cell frequencies, and functional responses to enteric bacteria

2019 ◽  
Vol 107 (1) ◽  
pp. 119-132 ◽  
Author(s):  
Stephanie M. Dillon ◽  
Jay Liu ◽  
Christine M. Purba ◽  
Allison J. Christians ◽  
Jon J. Kibbie ◽  
...  
Keyword(s):  
T Cell ◽  
Enteric Bacteria ◽  
T Helper Cell ◽  
Cd4 T Cell ◽  
Helper Cell ◽  
Cell Phenotype ◽  
T Helper ◽  
Functional Responses ◽  
Human Gut ◽  
Age Related

scholarly journals Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines.

1996 ◽  
Vol 183 (1) ◽  
pp. 87-97 ◽  
Author(s):  
L Zitvogel ◽  
J I Mayordomo ◽  
T Tjandrawan ◽  
A B DeLeo ◽  
M R Clarke ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Helper Cell ◽  
Helper Cell ◽  
T Helper ◽  
Tumor Models ◽  
Tumor Challenge ◽  
Ifn Gamma ◽  
Tumor Bearing ◽  
Pulsed Dc

Antigen presentation by host dendritic cells (DC) is critical for the initiation of adaptive immune responses. We have previously demonstrated in immunogenic murine tumor models that bone marrow (BM)-derived DC pulsed ex vivo with synthetic tumor-associated peptides, naturally expressed by tumor cells, serve as effective antitumor vaccines, protecting animals against an otherwise lethal tumor challenge (Mayordomo, J.I., T. Zorina, W.J. Storkus, C. Celluzzi, L.D. Falo, C.J. Melief, T. Ildstad, W.M. Kast, A.B. DeLeo, and M.T. Lotze. 1995. Nature Med. 1:1297-1302). However, T cell-defined epitopes have not been identified for most human cancers. To explore the utility of this approach in the treatment of tumors expressing as yet uncharacterized epitopes, syngeneic granulocyte/macrophage colony-stimulating factor-stimulated and BM-derived DC, pulsed with unfractionated acid-eluted tumor peptides (Storkus, W.J., H.J. Zeh III, R.D. Salter, and M.T. Lotze. 1993. J. Immunother. 14:94-103) were used to treat mice bearing spontaneous, established tumors. The adoptive transfer of 5 x 10(5) tumor peptide-pulsed DC dramatically suppressed the growth of weakly immunogenic tumors in day 4 to day 8 established MCA205 (H-2b) and TS/A (H-2d) tumor models, when applied in three biweekly intravenous injections. Using the immunogenic C3 (H-2b) tumor model in B6 mice, tumor peptide-pulsed DC therapy resulted in the erradication of established d14 tumors and long-term survival in 100% of treated animals. The DC-driven antitumor immune response was primarily cell mediated since the transfer of spleen cells, but not sera, from immunized mice efficiently protected sublethally irradiated naive mice against a subsequent tumor challenge. Furthermore, depletion of either CD4+ or CD8+ T cells from tumor-bearing mice before therapy totally suppressed the therapeutic efficacy of DC pulsed with tumor-derived peptides. Costimulation of the host cell-mediated antitumor immunity was critical since inoculation of the chimeric fusion protein CTLA4-Ig virtually abrogated the therapeutic effects of peptide-pulsed DC in vivo. The analysis of the cytokine pattern in the draining lymph nodes and spleens of tumor-bearing mice immunized with DC pulsed with tumor-eluted peptides revealed a marked upregulation of interleukin (IL) 4 and interferon (IFN) gamma production, as compared with mice immunized with DC alone or DC pulsed with irrelevant peptides. DC-induced antitumor effects were completely blocked by coadministration of neutralizing monoclonal antibody directed against T helper cell 1-associated cytokines (such as IL-12, tumor necrosis factor alpha, IFN-gamma), and eventually, but not initially, blocked by anti-mIL-4 mAb. Based on these results, we believe that DC pulsed with acid-eluted peptides derived from autologous tumors represents a novel approach to the treatment of established, weakly immunogenic tumors, and serves as a basis for designing clinical trials in cancer patients.

scholarly journals Cure of Progressive Murine Leishmaniasis: Interleukin 4 Dominance Is Abolished by Transient CD4+ T Cell Depletion and T Helper Cell Type 1–selective Cytokine Therapy

1999 ◽  
Vol 189 (12) ◽  
pp. 1895-1906 ◽  
Author(s):  
Frederick P. Heinzel ◽  
Ronald M. Rerko
Keyword(s):  
T Cell ◽  
Cellular Responses ◽  
T Helper Cell ◽  
Cd4 T Cell ◽  
Cell Depletion ◽  
Helper Cell ◽  
Cell Type ◽  
T Helper ◽  
T Cell Depletion ◽  
Helper Cell Type

Progressive infection with Leishmania major in susceptible BALB/c mice is mediated by interleukin (IL)-4–producing T helper cell type 2 (Th2) CD4+ T cells that, once established, become resistant to Th1-deviating therapies with recombinant (r)IL-12 and/or neutralizing anti–IL-4 antibodies. We sought to restore protective immunity in advanced leishmaniasis by depletion of Th2-biased CD4+ populations and by cytokine-directed reconstitution of Th1 cellular responses during lymphocyte recovery. Treatment with cytolytic GK1.5 anti-CD4 mAb alone did not reverse disease in 3 wk–infected BALB/c mice, but GK1.5 combined with anti–IL-4 antibody and intralesional rIL-12 cured cutaneous lesions in 80% of mice and established a Th1-polarized cytokine response to L. major antigen protective against reinfection. The curative effects of GK1.5 were not replaced by cytotoxic anti-CD8 monoclonal antibody 2.43 or nondepleting anti-CD4 mAb YTS177, confirming that depletion of CD4+ cells was specific and essential for therapeutic effect. Finally, combined CD4+ depletion and IL-4 neutralization were curative, indicating that neither increased parasite burden nor altered accessory cell function independently biased towards Th2 reconstitution in advanced leishmaniasis. Advanced leishmaniasis can be cured by T cell depletion and cytokine-directed recovery of Th1 cellular responses, suggesting novel interventions for other immune-mediated diseases and identifying distinct roles for CD4+ T cell and non-T cell in the maintenance of Th2 and Th1 phenotypes.

scholarly journals Expansion of T Helper Cell Subsets in Chronic Lymphocytic Leukemia Cell Co-Cultures with Nurselike Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1746-1746
Author(s):  
Alicia Vaca ◽  
Mariela Sivina ◽  
Karen Clise-Dwyer ◽  
Ekaterina Kim ◽  
Michael J Keating ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Helper Cells ◽  
Research Funding ◽  
T Helper Cell ◽  
T Cell Subsets ◽  
Helper Cell ◽  
T Helper ◽  
Helper Cells ◽  
Cell Counts

Background: In secondary lymphatic organs (SLO), chronic lymphocytic leukemia (CLL) cells form characteristic pseudo-follicles, also called proliferation centers, in which proliferating CLL cells are in intimate contact with CD4+ T helper cells. Despite evidence for a co-evolution of CLL cells and counterpart T helper cells, the prevalence and dynamics of T cell subsets, such as T follicular helper cells (TFH), T regulatory helper cells (TRegs) and IL-17-producing T helper cells (Th17) has not been characterized in detail. The CLL nurselike cell (NLC) model recapitulates key cellular and molecular interactions between CLL cells and the microenvironment in SLO, based on functional and gene expression studies, and represents a valid in vitro model for the SLO microenvironment in CLL. To gain insight into the potential role of T cells in CLL SLO, we utilized the NLC model to characterize T helper cell subsets and their dynamics in NLC co-cultures. Methods and Results: First, we quantified CD4+ and CD8+ T cell subsets in fresh peripheral blood mononuclear cell (PBMC) samples from 14 patients and then placed 1x107 PBMCs/ml in culture to establish NLC. We rechecked the relative proportion of CD4+ and CD8+ T cells, as well as absolute T cell counts, and their viability after 3, 6, 9, 12 and 14 days in NLC co-culture conditions. Interestingly, throughout the 14 days of culture, the number of T helper cells remained stable when compared to baseline samples. Next, we characterized T helper cell subsets in 25 different CLL samples, comparing CD4+ T cell subsets in freshly isolated CLL PBMC with matched samples harvested after 14 days of NLC culture. Samples were stained with subset-specific fluorescence-labeled antibody combinations, and analyzed by flow cytometry. NLC co-culture resulted in a significant expansion of TFH and TReg cells. TFH absolute cell counts assessed by flow cytometry using counting beads, increased from 9.4±2.2/μl at baseline to 29.0±5.9/μl in NLC co-cultures (n=14, p=0.001) and TReg from 17.0±3.3/μl to 51.0±15.0/μl (n=14, p=0.027). In contrast, Th17 absolute cell counts declined after 14 days of culture from 113.0±21.0/μl to 68.0±13.0/μl (n=14, p=0.001). Moreover, TH2 cells declined from 42.0±7.4/μl to 30.0±8.2/μl (n=14, p=0.005). Next, we analyzed for changes in TFH subsets (TFH1, TFH2 and TFH17). When compared to TFH cells from CLL PBMC, NLC culture resulted in a relative increase in TFH2 from 17.0±2.4% to 26.0±1.7% (n=25, p=0.013), and in TFH17 from 12.0±1.6% to 21.0±2.7% (n=25, p=0.006) In contrast, TFH1 frequency decreased after 14 days of culture (54.0±3.5% versus 34.0±2.9%, n=25, p=0.001). T follicular regulatory (TFr) cells also increase under co-culture conditions from undetectable to 4.8±1.9% (n=25, p=0.025)(Figure1). Looking at the maturity of CD4+ cells we noted a relative increase of central memory cells from 42.0±3.2% to 50.0±3.2% (n=25, p=0.023), whereas effector memory cells decreased from 34.0±3.4% to 26.0±2.7% (n=25, p=0.009), the fraction of naïve CD4+ cells remained unchanged. Next, we assessed the activation status of co-inhibitory receptors on CD3+CD4+ cells. We found a significant relative increase in CD4+ T cells expressing PD1 and CTLA-4 after 14 days of culture. Additionally, the TFH and TReg subsets demonstrated a significantly higher CTLA-4 expression after culture while TReg cells also addressed an increase in PD1 frequency. Furthermore, we observed a significantly higher CD28 expression on TFH and TReg subsets after 14 days of co-culture. Following, to address the residence and migration capacity of T cells in NLC co-cultures, we analyzed the CD69 and CD62L expression. Our results revealed significantly higher expression of CD69 in NLC co-cultures, whereas CD62L levels remained unchanged. Conclusion: The expansion of TFH and TReg cells in NLC co-cultures suggests the selection and clonal expansion of T cells that may support and engage in crosstalk with CLL cells. Additionally, the expansion of TFr and TFH17 cells could reflect a milieu of immune tolerance establishing in NLC co-cultures. Ongoing TCR sequencing of serial CD4+ T cell samples (baseline versus 14 days under NLC conditions) will characterize changes of clonal architecture in the T helper cell compartment, and will further improve our understanding of co-evolution of CLL and T helper cells. Disclosures Wierda: Gilead Sciences: Research Funding; Juno Therapeutics: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Janssen: Research Funding; Xencor: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Cyclcel: Research Funding; Loxo Oncology Inc.: Research Funding. Burger:Aptose Biosciences, Inc: Research Funding; BeiGene: Research Funding; Gilead Sciences: Research Funding; AstraZeneca: Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Pharmacyclics, an AbbVie company: Research Funding.

Differential expression of T-cell genes in blood and bone marrow between ITP patients and controls

2013 ◽  
Vol 109 (01) ◽  
pp. 112-117 ◽  
Author(s):  
Intawat Nookaew ◽  
Hans Wadenvik ◽  
Bob Olsson ◽  
Margareta Jernås
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Complement Activation ◽  
Peripheral Blood ◽  
T Helper Cell ◽  
Differentially Expressed ◽  
Helper Cell ◽  
T Helper

SummaryPrimary immune thrombocytopenia (ITP) is an autoimmune disease characterised by premature platelet destruction in spleen, liver and bone marrow and a diminished production of platelets. T-cells are important in all forms of autoimmunity including ITP; however, very little is known about T-cells in organs where platelets are destroyed. Our aim was to investigate differences in gene expression in peripheral blood-derived T-cells and bone marrow-derived T-cells between ITP patients and controls. T-cells and subsequent RNA were isolated from blood and bone marrow from chronic ITP patients and healthy controls followed by DNA microarray analysis. There were 1554 differentially expressed genes in peripheral blood-derived T-cells and 976 in bone marrow-derived T-cells between ITP patients and controls and three genes were verified with real-time PCR. Using Gene Ontology functional enrichment analysis we found that genes involved in growth, development, migration, chemotaxis, adhesion and apoptosis were enriched in bone marrow-derived T-cells in ITP. Immune-related genes involved in T-helper cell differentiation, T-cell chemotaxis, migration, immunoglobulin-mediated immune response and classical and alternative pathway complement activation were also enriched in bone marrow-derived T-cells in ITP. Only 213 T-cell genes were differentially expressed in both blood and bone marrow between ITP patients and controls. In conclusion, our findings show that genes involved in major pathophysiologic pathways in ITP such as T-helper cell differentiation, autoantibody response and complement activation are altered in bone marrow-derived T-cells in ITP patients compared with controls. This further supports the concept that bone marrow is an important compartment in ITP.

Activation of immunoregulatory lymphocytes obtained from patients with malignant gliomas

1987 ◽  
Vol 67 (2) ◽  
pp. 231-236 ◽  
Author(s):  
Lucinda H. Elliott ◽  
William H. Brooks ◽  
Thomas L. Roszman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Malignant Gliomas ◽  
Cell Subset ◽  
Suppressor Cells ◽  
T Helper Cell ◽  
Helper Cell ◽  
T Helper ◽  
Helper Cells ◽  
Helper Cell Subset

✓ The responsiveness of T cells and their subsets (T-helper cells and T-suppressor cells) obtained from patients with malignant gliomas was evaluated in an effort to further define the mechanism of their impaired host immunocompetence. This study demonstrates that peripheral blood lymphocytes obtained from these patients have impaired responsiveness to a variety of mitogens including phytohemagglutinin, concanavalin A, pokeweed mitogen, and anti-T3 monoclonal antibody. The impaired lymphocyte responsiveness does not result from the inability of these cells to express receptors for a specific mitogen or antibody. The mitogenic responsiveness of purified T cells is markedly reduced when compared to values obtained from control subjects. Therefore, the decreased T cell reactivity of patients with malignant gliomas does not result simply from a diminution in the absolute number of potentially responding lymphocytes. The mitogen reactivity of the T cell subsets, CD4+ helper cells, and CD8+ cytotoxic/suppressor cells was also investigated. These results demonstrate that the responsiveness of the CD4+ T-helper cell subset obtained from these patients is consistently diminished as compared to control values. In contrast, the reactivity of the CD8+ T cell subset was not nearly as dramatically impaired. Thus, these results indicate that the proliferative defect observed in T cells obtained from patients is located predominantly in the T-helper cell subset. Functional deficiencies in this important subpopulation of T lymphocytes may explain, in part, the presence of depressed immune responsiveness in patients with malignant glial tumors.

B7-H1 costimulation preferentially enhances CD28-independent T-helper cell function

Blood ◽  
2001 ◽  
Vol 97 (6) ◽  
pp. 1809-1816 ◽  
Author(s):  
Hideto Tamura ◽  
Haidong Dong ◽  
Gefeng Zhu ◽  
Gabriel L. Sica ◽  
Dallas B. Flies ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Helper Cell ◽  
Helper Cell ◽  
T Cell Proliferation ◽  
T Helper ◽  
Amino Acid Homology

B7-H1 is a recently described B7-like molecule that costimulates T-cell growth and cytokine secretion without binding to CD28, cytotoxic T-lymphocyte antigen-4 (CTLA-4), and inducible costimulator (ICOS). In this report, a mouse homologue of human B7-H1 is identified, and its immunologic functions are studied in vitro and in vivo. Mouse B7-H1 shares 69% amino acid homology to the human counterpart. Similar to human B7-H1, mouse B7-H1 can be induced to express on macrophages, T cells, and B cells and to enhance T-cell proliferation and secretion of interleukin-10 (IL-10), interferon-γ, and granulocyte-macrophage colony-stimulating factor but not IL-2 and IL-4. Furthermore, B7-H1 preferentially costimulates CD4+ T cells independently of CD28 and enhances mixed lymphocyte responses to allogeneic antigens. In contrast to B7-1, expression of B7-H1 on murine P815 tumor cells by transfection fails to increase allogeneic and syngeneic cytolytic T-cell responses in vitro and in vivo. Administration of B7-H1Ig fusion protein, however, enhances keyhole limpet hemocyanin– specific T-cell proliferation and 2,4,6-trinitrophenyl–specific immunoglobulin G2a antibody production. The study thus identifies a unique costimulatory pathway that preferentially affects T-helper cell functions.

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