Role of B7 signaling in the differentiation of naive CD4+ T cells to effector interleukin-4-producing T helper cells

1995 ◽  
Vol 14 (3) ◽  
pp. 176-188 ◽  
Author(s):  
William C. Gause ◽  
Joseph F. Urban ◽  
Peter Linsley ◽  
Pin Lu
Keyword(s):  
T Cells ◽  
T Helper Cells ◽  
Cd4 T Cells ◽  
Interleukin 4 ◽  
T Helper ◽  
Helper Cells

scholarly journals Role of T-Helper cells (CD4+ T Cells) in human immune system against some microbial infection: A mini review

2020 ◽  
Vol 3 (1) ◽  
pp. 026-029
Author(s):  
M Ali ◽  
M Lurwan ◽  
SN Halliru ◽  
AM Salihi
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Helper Cells ◽  
Cd4 T Cells ◽  
T Helper ◽  
Microbial Infection ◽  
Human Immune System ◽  
Helper Cells ◽  
Human Immune

Virus-Specific CD4+ T Cells Have Functional and Phenotypic Characteristics of Follicular T-Helper Cells in Patients With Acute and Chronic HCV Infections

2016 ◽  
Vol 150 (3) ◽  
pp. 696-706.e3 ◽  
Author(s):  
Bijan Raziorrouh ◽  
Kathrin Sacher ◽  
Rajiv G. Tawar ◽  
Florian Emmerich ◽  
Christoph Neumann-Haefelin ◽  
...  
Keyword(s):  
T Cells ◽  
T Helper Cells ◽  
Cd4 T Cells ◽  
T Helper ◽  
Phenotypic Characteristics ◽  
Helper Cells ◽  
Chronic Hcv ◽  
Follicular T Helper Cells

scholarly journals Immunological changes of T helper cells in flow cytometer‑sorted CD4+ T cells from patients with Hashimoto's thyroiditis

2018 ◽  
Author(s):  
Yanying Guo ◽  
Jazyra Zynat Zynat ◽  
Shuqing Xing ◽  
Liang Xin ◽  
Suli Li ◽  
...  
Keyword(s):  
T Cells ◽  
Hashimoto’S Thyroiditis ◽  
T Helper Cells ◽  
Cd4 T Cells ◽  
Flow Cytometer ◽  
Hashimoto's Thyroiditis ◽  
T Helper ◽  
Helper Cells ◽  
Immunological Changes

scholarly journals Treg-Resistant Cytotoxic CD4+ T Cells Dictate T Helper Cells in Their Vicinity: TH17 Skewing and Modulation of Proliferation

2021 ◽  
Vol 22 (11) ◽  
pp. 5660
Author(s):  
Cindy Hoeks ◽  
Marjan Vanheusden ◽  
Liesbet M. Peeters ◽  
Piet Stinissen ◽  
Bieke Broux ◽  
...  
Keyword(s):  
T Cells ◽  
Conditioned Medium ◽  
T Helper Cells ◽  
Cd4 T Cells ◽  
Cell Contact ◽  
T Helper ◽  
Th Cells ◽  
Inflammatory Microenvironment ◽  
Helper Cells

Cytotoxic CD4+ T cells (CD4 CTL) are terminally differentiated T helper cells that contribute to autoimmune diseases, such as multiple sclerosis. We developed a novel triple co-culture transwell assay to study mutual interactions between CD4 CTL, conventional TH cells, and regulatory T cells (Tregs) simultaneously. We show that, while CD4 CTL are resistant to suppression by Tregs in vitro, the conditioned medium of CD4 CTL accentuates the suppressive phenotype of Tregs by upregulating IL-10, Granzyme B, CTLA-4, and PD-1. We demonstrate that CD4 CTL conditioned medium skews memory TH cells to a TH17 phenotype, suggesting that the CD4 CTL induce bystander polarization. In our triple co-culture assay, the CD4 CTL secretome promotes the proliferation of TH cells, even in the presence of Tregs. However, when cell−cell contact is established between CD4 CTL and TH cells, the proliferation of TH cells is no longer increased and Treg-mediated suppression is restored. Taken together, our results suggest that when TH cells acquire cytotoxic properties, these Treg-resistant CD4 CTL affect the proliferation and phenotype of conventional TH cells in their vicinity. By creating such a pro-inflammatory microenvironment, CD4 CTL may favor their own persistence and expansion, and that of other potentially pathogenic TH cells, thereby contributing to pathogenic responses in autoimmune disorders.

scholarly journals Gene Regulatory Network of Human GM-CSF-Secreting T Helper Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-24
Author(s):  
Szabolcs Éliás ◽  
Angelika Schmidt ◽  
David Gomez-Cabrero ◽  
Jesper Tegnér
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Autoimmune Diseases ◽  
T Helper Cells ◽  
Cd4 T Cells ◽  
T Helper ◽  
Gm Csf ◽  
Helper Cells ◽  
Gene Regulatory ◽  
Memory Cd4 T Cells

GM-CSF produced by autoreactive CD4-positive T helper cells is involved in the pathogenesis of autoimmune diseases, such as multiple sclerosis. However, the molecular regulators that establish and maintain the features of GM-CSF-positive CD4 T cells are unknown. In order to identify these regulators, we isolated human GM-CSF-producing CD4 T cells from human peripheral blood by using a cytokine capture assay. We compared these cells to the corresponding GM-CSF-negative fraction, and furthermore, we studied naïve CD4 T cells, memory CD4 T cells, and bulk CD4 T cells from the same individuals as additional control cell populations. As a result, we provide a rich resource of integrated chromatin accessibility (ATAC-seq) and transcriptome (RNA-seq) data from these primary human CD4 T cell subsets and we show that the identified signatures are associated with human autoimmune diseases, especially multiple sclerosis. By combining information about mRNA expression, DNA accessibility, and predicted transcription factor binding, we reconstructed directed gene regulatory networks connecting transcription factors to their targets, which comprise putative key regulators of human GM-CSF-positive CD4 T cells as well as memory CD4 T cells. Our results suggest potential therapeutic targets to be investigated in the future in human autoimmune disease.

Immunologic Recovery after Nonmyeloablative (NM) Conditioning: A Comparison between Related Versus Unrelated Donor Hematopoietic Cell Transplantation (HCT).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1402-1402 ◽  
Author(s):  
Frederic Baron ◽  
M. Maris ◽  
J. Storek ◽  
M. Metcalf ◽  
K. White ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cd8 T Cells ◽  
T Helper Cells ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Infectious Complications ◽  
T Helper ◽  
Helper Cells ◽  
Cmv Reactivation

Abstract Background. After NM conditioning, recipients of peripheral blood stem cells (PBSC) from HLA-identical siblings (MRD) have persistent recipient-derived immunity leading to lower incidence of early infectious complications in comparison with patients (pts) given myeloablative conditioning (Exp Hematol31: 941, 2003). Because of greater genetic disparities, intensity and duration of postgrafting immunosuppression (IS) have been increased in pts given PBSC from HLA-matched unrelated donors (URD), in order to both promote engraftment and decrease risk of GVHD. This study was done to determine how this increased/extended postgrafting IS affected immune recovery and infectious complications. Methods. We compared immunologic recovery in 51 pts given PBSC from MRD (n=51) and 43 pts given grafts from URD after 2 Gy TBI +/− fludarabine. Postgrafting IS concisted of mycophenolate mofetil (MMF, given TID for 40 days followed by a 56 day taper in URD recipients, and BID for 28 days in MRD recipients) and cyclosporin. The counts of blood mononuclear cell subsets were assessed by flow cytometry; frequency of CMV-specific CD4 T-helper cells among CMV seropositive pts or CMV-seronegative pts with CMV-seropositive donors was determined by lymphoproliferation (LPR), limiting-dilution assays (LDA), and intracellular interferon-gamma (IF) production (ICC). Analyses were performed on days 30, 80, 180 and 365 after HCT. Results. On day 30 after HCT, URD recipients had lower counts of total B-cells (P=.02), naive B-cells (P=.03), memory B-cells (P=.01), CD4 T-cells (P=.06), naive CD4 T-cells (P=.05), memory CD4 T-cells (P=.003), CD8 T-cells (P=.0004), naive CD8 T-cells (P=.08) and memory CD8 T-cells (P=.006) than MRD recipients. However, the counts of mononuclear cell subsets were similar in URD and MRD recipients from day 30 to day 365 after HCT. Similarly, the frequency of CMV-specific T-helper cells was significantly lower in URD than in MRD recipients on day 30 after HCT as determined by LPR (median CPM 17 versus 92 per 1000 CD4 T-cells, P=.02), LDA (median 22307 versus 73251 CMV-CD4 T-helper cells per L, P=.7) and ICC (median 0.26% versus 0.93% CD4 cells positive for IF, P=.02). This delay in CMV-specific immune reconstitution translated into increased frequency of CMV-reactivation (and increased use of preemptive antiviral therapy [PET]) among CMV-seropositive pts or CMV-seronegative pts with CMV seropositive donors given URD grafts (63%) compared with MRD (33%) recipients (P=.02) the first 100 days after HCT. This did not lead to increased CMV disease among URD recipients (1 episode) compared with MRD recipients (1 episode), demonstrating that PET was similarly effective in preventing CMV diseases in both groups. After day 100, there were no statistically significant differences in immune reconstitution parameters. Incidence figures for non-CMV viral infections, bacteremias, and invasive fungal infections were not significantly different between the 2 groups. A multivariate analysis assessing pre-transplant and post-transplant factors associated with immunologic recovery after NM conditioning will be presented. Conclusions. Despite similar NM conditioning regimens, immunologic recovery was delayed among URD recipients in comparison to MRD recipients, probably because of increased/extended postgrafting IS. This led to increased incidence of CMV reactivation among URD recipients. CMV infection and immune reconstitution pattern appear similar to those seen after myeloablative PBSC transplantation.

Peripheral B Cells from Patients with MGUS and Multiple Myeloma (MM) Can Be Stimulated by Paraprotein-Target Specific T-Helper Cells to Produce Paraprotein-Identical Monoclonal Antibodies: Rationale for PARs, a Novel Therapeutic Approach with Ultimate Specificity in MGUS/MM

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1817-1817
Author(s):  
Frank Neumann ◽  
Boris Kubuschok ◽  
Klaus-Dieter Preuss ◽  
Claudia Schormann ◽  
Michael Pfreundschuh
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
T Helper Cells ◽  
Plasma Cells ◽  
T Helper ◽  
Helper Cells ◽  
Hla Dr ◽  
Peripheral B Cells

Abstract Background: Paratarg-7 (P-7) is the antigenic target of paraproteins(Preuss et al. Int J Cancer 2009;125:656-61) from 15% of European and 37% of African-American MGUS/MM patients, stronlgy supporting a role of P-7 in the pathogenesis of MGUS/MM via chronic auto-antigenic stimulation. All patients with P-7 specific paraproteins are carriers of the hyperphosphorylated version of p-7 (pP-7). We recently identified pP-7 specific T-helper cells which were restricted by certain "permissive" HLA-DR haplotypes (Neumann et al., Int J Cancer 2015; 137:1076-1084). These HLA-DR subtypes are overrepresented among patients with P-7 specific paraproteins compared to the corresponding normal population indicating that there are two prerequisites for the development of MGUS/MM with a P-7 specific paraprotein: 1st carriership of pP-7 and 2nd a permissive HLA-DR subtype. We now investigated the functional role of the pP-7 specific T-helper cells and their interaction with peripheral B cells with cognate specificity. Methods: Three patients with MGUS or MM, respectively, with a P-7 specific paraprotein and pP-7 specific T-helper cells were included in this study so far. In addition, the B cells from one healthy pP-7 carrying son of one of the patients were also analyzed. In vitro stimulation of antigen-specific peripheral B cells by pP-7 specific T-helper cells followed a modified protocol previously described by Lanzavecchia et al. (Eur J Immunol. 1983; 13:733-738). To this end, CD19+ B cells and CD3+ T cells were magnetically isolated from the proband's PBMC. T cells were replaced by corresponding T-helper cell clones. Results: In all patients studied, the autologous pP-7 specific T-helper cells stimulated the peripheral B cells to produce P-7 specific antibodies. The P-7 specific B-cell responses were monoclonal and the immunoglobulin type was the same as the paraprotein of the corresponding patient. In contrast, B-cell stimulation with CMV-pp65 specific T-helper cells used as controls always induced an antigen-specific, yet polyclonal response. When the peripheral B cells of a pP-7 carrying patient's son were also stimulated with pP-7 specific T-helper cells, they induced - in contrast to the mother - a polyclonal P-7 specific antibody response in his B cells, even though mother and son shared a "permissive" HLA-DR haplotype (HLA-DRB1*1301). Conclusion: In patients with MGUS/MM monoclonal B cells are found in the peripheral blood that can be induced to produce monoclonal antibodies identical to the serum paraprotein by T-helper cells with specificity for the antigenic target of the paraprotein. This does not only support an indispensable role of these T-helper cells in the pathogenesis of MGUS/MM via chronic antigenic stimulation, it also proves that precursors of the malignant plasma cells can be found in the peripheral blood that might fuel the development of malignant plasma cells. Cytogenetic and molecular genetic analyses are underway to determine if these precursor B-cells share the malignant genotype of their malignant plasma cells. These B cells can now be targeted by PARs (p araprotein a ntigens for r everse targeting) conjugated to toxins, as parts of bispecific constructs (PAR/CD3 or PAR/CD16) and/or PAR/CAR T cells. Use of PARs can be envisaged prophylactically for carriers of modified autoantigens like pP-7 with a permissive HLA-DR haplotype and a monoclonal B-cell response in vitro or in MM patients achieving a VGPR or CR after treatment for the prevention of relapse. Disclosures No relevant conflicts of interest to declare.

scholarly journals Chemotherapy rescues tumor-driven aberrant CD4+ T-cell differentiation and restores an activated polyfunctional helper phenotype

Blood ◽  
2010 ◽  
Vol 115 (12) ◽  
pp. 2397-2406 ◽  
Author(s):  
Zhi-Chun Ding ◽  
Bruce R. Blazar ◽  
Andrew L. Mellor ◽  
David H. Munn ◽  
Gang Zhou
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Helper Cells ◽  
Cd4 T Cells ◽  
T Helper ◽  
Effector Cells ◽  
Helper Cells ◽  
Interleukin 7 ◽  
Programmed Death

The functional development of tumor-specific CD4+ T cells has a critical impact on the outcome of antitumor immune responses. Adoptive immunotherapy involving tumor-specific CD4+ T cells has shown encouraging clinical benefits in some cancer patients. To mount an effective antitumor immunity, it is desirable to elicit activated type 1 T helper cells. Here, we report that type 1 T helper cell–like effector cells that arose in tumor-bearing hosts progressively expressed programmed death 1 during tumor growth. The programmed death 1hi effector cells displayed a dysfunctional phenotype, characterized by selective down-regulation of interleukin-7 receptor, heightened apoptosis, and poor antitumor efficacy. This tumor-driven aberrant T-cell response could be prevented by a single dose of the widely used chemotherapy agent cyclophosphamide. We show that chemotherapy conditioned the host environment, creating a transient window for optimal effector differentiation for adoptively transferred CD4+ T cells. This robust effector differentiation, which was antigen-driven and mechanistically dependent on an intact host response to type I interferon, gave rise to activated polyfunctional T helper cells with high interleukin-7 receptor, rapid clonal expansion, and potent antitumor activity against established B-cell lymphomas. We hypothesize that prevention of tumor-induced effector cell dysfunction is a major mechanism contributing to the efficacy of combined chemoimmunotherapy.

scholarly journals POS0429 INTERLEUKIN-4 ACTIVATES EOSINOPHILS AND CCR3-POSITIVE T HELPER CELLS MIGRATION TO FASCIA AND PROMOTES FIBROSIS IN EOSINOPHILIC FASCIITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 443.1-443
Author(s):  
M. Hosonuma ◽  
T. Isozaki ◽  
H. Furuya ◽  
Y. Yamazaki ◽  
Y. Ikari ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Growth Factor ◽  
Conditioned Medium ◽  
T Helper Cells ◽  
Post Treatment ◽  
Interleukin 4 ◽  
Eosinophilic Fasciitis ◽  
T Helper

Background:Eosinophilic fasciitis (EF) is a rare disease that causes inflammation and fibrosis mainly in the fascia of the extremities with eosinophilia. It has been reported that the hypertrophied fascia in EF shows inflammatory cell infiltration by the lymphocytes and eosinophils and increased expression of fibrosis-related cytokines genes in fibroblast [1]. However, its pathophysiology in the fascia remains unresolved.Objectives:Therefore, we focused on fascial fibroblasts and aimed to determine the role of interleukin-4 (IL-4) in eosinophil and helper T cell infiltration and fibrosis in fascial fibroblast in EF.Methods:Fascial fibroblasts were obtained from fascia biopsy of a patient with EF, and were stimulated with pre- and post-treatment serum of a patient with EF and healthy control, followed by microarray to analyze gene expression. Fascial fibroblasts were stimulated with IL-4 10 ng/mL, and gene expression of IL-4 receptor and CCR3 ligands, CCL7 and CCL11 were measured by qPCR. Transforming growth factor (TGF) -β and periostin in the pre- and post-treatment serum of a patient with EF and conditioned medium of fascial fibroblasts stimulated with IL-4 were measured by ELISA. To examine the role of IL-4 in proliferation, we performed in proliferation assays using fascial fibroblasts treated with IL-4. CCR3-positive T cells in the fascial tissue of EF, dermatomyositis, and polymyositis patients were evaluated by immunostaining.Results:By microarray analysis, CCL7 and CCL11 expression of fascial fibroblasts stimulated with pre-treatment EF serum was higher than that in post-treatment EF serum and control serum. CCL7 and CCL11 mRNA in IL-4 stimulated facial fibroblasts were increased by 5.1-fold and 7.3-fold, respectively. TGF-β and periostin in IL-4 stimulated facial fibroblast conditioned medium were also increased. In addition, TGF-β and periostin in EF serum were gradually decreased by treatment for 4 and 10 weeks, compared to before treatment. Finally, fascial fibroblast proliferation was significantly increased by stimulation with IL-4. Furthermore, infiltration of CCR3-positive T cells was specific to the fascial tissue of EF.Conclusion:In EF, IL-4 enhances the production of CCR3 ligands, TGF-β, and periostin from fascial fibroblasts. As a result, it promotes the migration of eosinophils and CCR3-positive T helper cells to the fascia and fibrosis. These results suggest that inhibition of IL-4 pathway could be a novel strategy for eosinophilic fasciitis.References:[1]Igarashi A, Nashiro K, Kikuchi K, et al. Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders. J Invest Dermatol. 1996 Apr;106(4):729-33.Disclosure of Interests:None declared

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