scholarly journals Idiotype-recognizing T helper cells that are not idiotype specific.

1983 ◽  
Vol 158 (3) ◽  
pp. 811-821 ◽  
Author(s):  
M McNamara ◽  
H Kohler
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cell Response ◽  
T Helper Cells ◽  
Helper Cell ◽  
T Helper ◽  
Helper Cells ◽  
Limiting Dilution ◽  
Selection Of ◽  
B Cell Response

In this study T helper cells that recognize idiotypes as carriers for a hapten-specific B cell response were analyzed under limiting dilution conditions. T helper cells, induced by phosphorylcholine-hemocyanin (PC-Hy) priming, recognize trinitrophenylated TEPC-15 and MOPC-167 (TNP-T15, TNP-167) equally well. Limiting dilution analysis indicates identical frequencies of helper cells for TNP-T15 and TNP-167. Double immunization protocols using TNP-T15 and TNP-167 fail to demonstrate additive effects. Inhibition of carrier recognition in vitro using free hapten, PC, and unconjugated T15 or M167 indicates identical specificities of helper cells for T15 and M167. Collectively, these results provide strong evidence that PC-Hy priming induces only one population of idiotype-recognizing helper cells that are unable to distinguish between the T15 and the M167 idiotopes. The helper cell induction circuit was further analyzed. PC-Hy priming induces T15/167-specific helper T cells in X-linked immune defect-expressing F1 mice. This indicates that a B cell response to PC is not required to induce idiotype-recognizing T cells. Adoptive cotransfer of B cells from PC-Hy-primed mice together with normal T cells fails to induce idiotype-recognizing T cells. These results indicate the existence of a T helper1-T helper2 induction loop. In this scheme, the T helper1 cell carries T15-like receptors and the T helper2 cells, anti-T15-like receptors. Monoclonal antiidiotypic antibodies specific for T15 also induce a T15/167-recognizing T helper cell population. This finding demonstrates that idiotope-specific priming induces non-idiotype-specific T cells. Evidently, the idiotypic T cell network is based on a different selection of idiotope determinants than the selection of the B cell idiotype network.

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

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
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.

scholarly journals Role of accessory cells in cytokine production by T cells in chronic B- cell lymphocytic leukemia

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 1115-1123 ◽  
Author(s):  
T Decker ◽  
T Flohr ◽  
P Trautmann ◽  
MJ Aman ◽  
W Holter ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
T Helper Cells ◽  
Cytokine Production ◽  
Lymphocytic Leukemia ◽  
T Helper ◽  
Ifn Gamma ◽  
Helper Cells ◽  
Accessory Cells ◽  
Normal Individuals

Abstract We investigated the production of cytokines by highly purified T helper cells from B-cell chronic lymphocytic leukemia (B-CLL) patients stimulated by different activation pathways, and we studied the influence of various accessory cell populations on the pattern of the secretion of cytokines, including interleukin (IL)-2, IL-4, interferon- gamma (IFN-gamma), and IL-10. Neither a qualitative nor a quantitative difference in cytokine production and proliferative capacity was observed in CLL-derived purified T cells compared with normal individuals, when T cells were stimulated by different pathways, including CD3, CD2, and costimulation with CD28. Addition of autologous accessory cells (aAC), however, dramatically influenced the cytokine pattern of normal versus B-CLL-derived T cells. CLL cells as aAC caused a marked increase of IL-2, whereas IFN-gamma was only slightly induced and IL-4 was not influenced. In contrast, in normal individuals addition of aAC, which predominantly consisted of monocytes, resulted in a significant increase of IFN-gamma and a reduction of IL-4 secretion. IL-2 production was inhibited by higher concentrations of aAC. The increased stimulation of IL-2 production by CLL cells was not specific to the leukemic cell population, as purified B cells from normal individuals had the same effect. On the other hand, purified monocytes from CLL patients and controls both induced IFN-gamma production and inhibited IL-4 secretion. After antigen-specific stimulation with tetanus toxoid, cytokine secretion was influenced by the type of aAC in a similar pattern. We conclude that T helper cells derived from patients with B-CLL are intrinsically normal and that the predominance of B cells as accessory cells in CLL significantly alters the immune function of T helper cells in vitro.

scholarly journals Tissue-resident CD4+ T helper cells assist the development of protective respiratory B and CD8+ T cell memory responses

2021 ◽  
Vol 6 (55) ◽  
pp. eabb6852
Author(s):  
Young Min Son ◽  
In Su Cheon ◽  
Yue Wu ◽  
Chaofan Li ◽  
Zheng Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Helper Cells ◽  
Critical Role ◽  
Cell Formation ◽  
Influenza Virus Infection ◽  
T Helper ◽  
Helper Cells ◽  
Cell Immunity

Much remains unknown about the roles of CD4+ T helper cells in shaping localized memory B cell and CD8+ T cell immunity in the mucosal tissues. Here, we report that lung T helper cells provide local assistance for the optimal development of tissue-resident memory B and CD8+ T cells after the resolution of primary influenza virus infection. We have identified a population of T cells in the lung that exhibit characteristics of both follicular T helper and TRM cells, and we have termed these cells as resident helper T (TRH) cells. Optimal TRH cell formation was dependent on transcription factors involved in T follicular helper and resident memory T cell development including BCL6 and Bhlhe40. We show that TRH cells deliver local help to CD8+ T cells through IL-21–dependent mechanisms. Our data have uncovered the presence of a tissue-resident helper T cell population in the lung that plays a critical role in promoting the development of protective B cell and CD8+ T cell responses.

scholarly journals Role of accessory cells in cytokine production by T cells in chronic B- cell lymphocytic leukemia

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 1115-1123
Author(s):  
T Decker ◽  
T Flohr ◽  
P Trautmann ◽  
MJ Aman ◽  
W Holter ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
T Helper Cells ◽  
Cytokine Production ◽  
Lymphocytic Leukemia ◽  
T Helper ◽  
Ifn Gamma ◽  
Helper Cells ◽  
Accessory Cells ◽  
Normal Individuals

We investigated the production of cytokines by highly purified T helper cells from B-cell chronic lymphocytic leukemia (B-CLL) patients stimulated by different activation pathways, and we studied the influence of various accessory cell populations on the pattern of the secretion of cytokines, including interleukin (IL)-2, IL-4, interferon- gamma (IFN-gamma), and IL-10. Neither a qualitative nor a quantitative difference in cytokine production and proliferative capacity was observed in CLL-derived purified T cells compared with normal individuals, when T cells were stimulated by different pathways, including CD3, CD2, and costimulation with CD28. Addition of autologous accessory cells (aAC), however, dramatically influenced the cytokine pattern of normal versus B-CLL-derived T cells. CLL cells as aAC caused a marked increase of IL-2, whereas IFN-gamma was only slightly induced and IL-4 was not influenced. In contrast, in normal individuals addition of aAC, which predominantly consisted of monocytes, resulted in a significant increase of IFN-gamma and a reduction of IL-4 secretion. IL-2 production was inhibited by higher concentrations of aAC. The increased stimulation of IL-2 production by CLL cells was not specific to the leukemic cell population, as purified B cells from normal individuals had the same effect. On the other hand, purified monocytes from CLL patients and controls both induced IFN-gamma production and inhibited IL-4 secretion. After antigen-specific stimulation with tetanus toxoid, cytokine secretion was influenced by the type of aAC in a similar pattern. We conclude that T helper cells derived from patients with B-CLL are intrinsically normal and that the predominance of B cells as accessory cells in CLL significantly alters the immune function of T helper cells in vitro.

Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help

Blood ◽  
2005 ◽  
Vol 106 (6) ◽  
pp. 1924-1931 ◽  
Author(s):  
Svenja Hardtke ◽  
Lars Ohl ◽  
Reinhold Förster
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Helper Cells ◽  
Cell Area ◽  
T Helper ◽  
Helper Cells ◽  
Follicular T Helper Cells ◽  
Cell Follicle

Abstract The production of high-affinity antibodies to T-dependent antigens requires the interaction of B cells and T helper cells expressing receptors specific for the same antigen. Although several mechanisms have been elucidated that regulate B-cell trafficking within lymphoid organs, less is known about molecular cues that guide the small subpopulation of CD4+ follicular T helper cells to B-cell follicles. Using adoptive transfer of transgenic T cells in mice, we demonstrate that antigen-induced activation leads to a finely tuned positioning of T cells either to the T-cell area or the B-cell follicle. We show that expression of CXCR5 is indispensable for T cells to enter B-cell follicles, whereas expression of CCR7 provides a counteracting signal to retain activated T cells in the T-cell area. Although only few T cells transiently migrate from the T-cell area to the B-cell follicle of peripheral lymph nodes following antigenic challenge, this step is essential to provide the help B cells require to produce antibodies efficiently. Thus, we demonstrate that the balanced expression of CCR7 and CXCR5 determines the positioning and proper function of follicular T helper cells.

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.

scholarly journals Regulatory idiotypes. T helper cells recognize a shared VH idiotope on phosphorylcholine-specific antibodies.

1982 ◽  
Vol 156 (2) ◽  
pp. 539-549 ◽  
Author(s):  
K Gleason ◽  
H Köhler
Keyword(s):  
T Cells ◽  
B Cell ◽  
Binding Site ◽  
T Helper Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
T Helper ◽  
Binding Studies ◽  
Heavy Chains ◽  
Helper Cells ◽  
Myeloma Proteins

Priming of BALB/c mice with phosphorylcholine-hemocyanin (PC-Hy) induces T helper cells that are detected in splenic fragment cultures responding to immunization with trinitrophenylated PC-binding myeloma proteins, TEPC 15 (TNP-T15) and MOPC 167 (TNP-M167). Trinitrophenylation did not alter the binding site, idiotype, or isotype of the antibodies as demonstrated by binding studies. To assay idiotype-recognizing helper cells, Ly-2.2-depleted T cells from PC-Hy-primed donor mice were transferred to syngeneic athymic mice. Splenic anti-trinitrophenol fragment cultures were prepared from the nude recipients, and the response to TNP-T15 and TNP-M167 was measured by enzyme-linked immunosorbent assay. The number of responding fragments is dependent on the number of transferred primed T cells. The homing efficiency of 51Cr-labeled helper cells into the spleen of nude recipients was determined. The frequencies of T helper cells taken from PC-Hy-primed donors required for a B cell response to TNP-T15 or TNP-M167 were indistinguishable. The fine specificity of the anti-PC idiotype-recognizing T helper cells was studied by adding hapten (PC) or unconjugated myeloma proteins to fragment cultures as inhibitors at the time of immunization. PC and PC-bovine serum albumin, as well as T15 and M167, inhibited the helper function in vitro. Furthermore, free heavy chains of T15 and M167 partially inhibited T help, but free light chains of both idiotypes had no effect. These findings collectively show that T helper cells, induced by priming with antigen, recognize a shared idiotypic determination on T15 and M167 that is part of the PC binding site. The heavy chains of T15 and M167 appears to be the major structural component of this determinant. Evidently, T helper cells can recognize a shared determinant that is present on idiotypically different myeloma proteins. This determinant appears to be conserved throughout evolutionary and somatic mutations. The role of this shared, binding site-related idiotypic determinant as a regulatory idiotype in T-B cell interaction is discussed.

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.

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