scholarly journals Regulatory T cells can migrate to follicles upon T cell activation and suppress GC-Th cells and GC-Th cell-driven B cell responses

2005 ◽  
Vol 115 (1) ◽  
pp. 195-195
Author(s):  
Hyung W. Lim ◽  
Peter Hillsamer ◽  
Chang H. Kim
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Th Cells ◽  
Cell Responses ◽  
Th Cell ◽  
B Cell Responses

Distinct Patterns of Systemic Immune Dysregulation in Indolent B Cell Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3780-3780
Author(s):  
Petros Christopoulos ◽  
Dietmar Pfeifer ◽  
Kilian Bartholomé ◽  
Marie Follo ◽  
Paul Fisch ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Dysregulation ◽  
Cell Phenotype ◽  
Cd4 Cells ◽  
Th Cells

Abstract Mutual interactions of the neoplastic clone with the non-neoplastic immune system may influence immune function and the clinical behaviour of lymphoma. Individuals with immunodeficiency or autoimmune diseases have an increased risk for lymphoma development. The immune microenvironment appears to have a major influence on the prognosis of indolent lymphomas. Conversely, leukemic lymphomas may also cause immunodeficiency: In CLL, direct lymphoma-T cell interactions, which may occur ubiquitously, induce defects in T cell functions (Görgün et al., 2005). We demonstrate here a systemic perturbance of cellular immunity in a prospective study in patients with untreated de novo, limited-stage, non-leukemic indolent B cell lymphomas. Calibrated, quantitative flow cytometry showed a significant reduction of circulating T helper (TH) cells in follicular (FL; n=11; p<0.005) and extranodal marginal zone (eMZL; n=7; p<0.05) lymphomas compared to age-matched healthy persons. Naive TH cells were strongest reduced to 51% (p=0.002) in FL and 24% (p=0.002) in eMZL. Regulatory T cells (CD4loCD25hi; CD4+FoxP3+) were affected less (p=0.04). T cell receptor excision circles within CD4+ cells as assessed by quantitative PCR were not altered in lymphoma patients, indicating neither increased increased thymic output nor homeostatic T cell proliferation to compensate the contracted pool of naive T cells. The TH memory compartments, the global numbers and subsets of CD8+ T (TC) cells, NK, and NKT cells were normal. The peripheral lymphocyte composition was altered differently in early CLL (stage Binet A; leukocyte counts < 28/nl; n=9) with increased TH (p=0.04) and TC (p=0.0002) cells. No significant changes in lymphocyte subsets were noted in monoclonal gammopathy of unknown significance (MGUS; n=6). The functional T cell phenotype in vivo was altered in eMZL as indicated by four- and twofold increased HLA-DR+ TH (p<0.02) and TC (p=0.05) cells. This T cell activation may also explain an increased fraction of terminally differentiated (CD45RA+CD27−) TC cells (p<0.05). Qualitatively similar abnormalities were seen in FL, where activated TH cells were more frequent (p<0.005), and in CLL, where activated TC cells were increased (p=0.04), but not in MGUS. Finally, an increased T cell activation may effect senescence, which was evident by elevated fractions of CD57+ and CD28− cells within the TC compartment of FL/eMZL (p<0.05) and CLL (p<0.005) patients. The activated T cell phenotype was paralleled by increased upregulation of activation markers (CD25, OX40, CD95, p<0.005 for each) and proliferation (p<0.005) by purified CD4 cells from FL/eMZL patients in a standardized anti-CD3/anti-CD28 stimulation culture. None of these parameters was significantly aberrant in CLL. Expression of the activation marker CD69, which is downregulated rapidly after T cell activation, was markedly reduced both in vivo and after in vitro stimulation in FL/eMZL. Collectively, these data demonstrate a global, “preactivated” and presenescent state of peripheral T cells in non-leukemic, indolent T cell lymphomas. Finally, a shift towards TH2 cells was evident in FL/eMZL TH stimulation cultures by increased secretion of IL-4 and IL-5 (p=0.01), but not of IL-2, IFNg, IL-10, and TNFa. This cytokine pattern was absent in CLL and MGUS. The TH2 shift, and the qualitative difference in the immune status in FL/eMZL versus CLL was validated by gene expression profiling of stimulated TH cells with Affymetrix U133 arrays. KEGG annotation revealed decreased expression of proximal TCR signalling molecules and TCR/CD28 transduction pathways with the exception of NFAT in FL/eMZL and CLL. Extensive correlative analyses between gene expression profiles and functional data indicated at least two distinct immune dysregulation patterns: A hyperreactivity/TH2 pattern which is operational even in early disease; and a B cell burden-dependent impairment of TCR signalling. The latter pattern predominates in CLL, which has a comparatively high B cell burden in early disease. These data are clinically relevant since we demonstrate in a prospective trial that untreated FL/eMZL patients fail to respond to protective hepatitis B vaccination (p<0.005). Precise definition of functional T cell defects will permit to study the causes, the prognostic influence, and potential reversibility of immune dysregulation patterns in indolent B cell lymphomas.

scholarly journals Effects of Friend Virus Infection and Regulatory T Cells on the Antigen Presentation Function of B Cells

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Tyler C. Moore ◽  
Ronald J. Messer ◽  
Lorena M. Gonzaga ◽  
Jennifer M. Mather ◽  
Aaron B. Carmody ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Regulatory T Cells ◽  
B Cell ◽  
Cell Activation ◽  
T Cell Responses ◽  
B Cell Activation ◽  
Friend Virus ◽  
Cell Responses

ABSTRACTFriend virus (FV) is a naturally occurring mouse retrovirus that infects dividing cells of the hematopoietic lineage, including antigen-presenting cells (APCs). The infection of APCs by viruses often induces their dysfunction, and it has been shown that FV infection reduces the ability of dendritic cells (DCs) to prime critical CD8+T cell responses. Nonetheless, mice mount vigorous CD8+T cell responses, so we investigated whether B cells might serve as alternative APCs during FV infection. Directex vivoanalysis of B cells from FV-infected mice revealed that infected but not uninfected B cells upregulated expression of the costimulatory molecules CD80, CD86, and CD40, as well as major histocompatibility complex class II (MHC-II) molecules. Furthermore,in vitrostudies showed that, compared to uninfected B cells from the same mice, the FV-infected B cells had significantly enhanced APC function, as measured by their capacity to prime CD8+T cell activation and proliferation. Thus, in contrast to DCs, infection of B cells with FV enhanced their APC capacity and ability to stimulate the CD8+T cell responses essential for virus control. FV infections also induce the activation and expansion of regulatory T cells (Tregs), so it was of interest to determine the impact of Tregs on B cell activation. The upregulation of costimulatory molecule expression and APC function of B cells was even more strongly enhanced byin vivodepletion of regulatory T cells than infection. Thus, Tregs exert potent homeostatic suppression of B cell activation that is partially overcome by FV infection.IMPORTANCEThe primary role of B cells in immunity is considered the production of pathogen-specific antibodies, but another, less-well-studied, function of B cells is to present foreign antigens to T cells to stimulate their activation and proliferation. Dendritic cells (DCs) are considered the most important antigen-presenting cells (APCs) for CD8+T cells, but DCs lose APC function when infected with Friend virus (FV), a model retrovirus of mice. Interestingly, B cells were better able to stimulate CD8+T cell responses when they were infected with FV. We also found that the activation status of B cells under homeostatic conditions was potently modulated by regulatory T cells. This study illustrates an important link between B cell and T cell responses and illustrates an additional mechanism by which regulatory T cells suppress critical T cell responses during viral infections.

scholarly journals CD32+CD4+ T Cells Sharing B Cell Properties Increase With Simian Immunodeficiency Virus Replication in Lymphoid Tissues

2021 ◽  
Vol 12 ◽  
Author(s):  
Nicolas Huot ◽  
Philippe Rascle ◽  
Cyril Planchais ◽  
Vanessa Contreras ◽  
Caroline Passaes ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Lymphoid Tissues ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Siv Infection

CD4 T cell responses constitute an important component of adaptive immunity and are critical regulators of anti-microbial protection. CD4+ T cells expressing CD32a have been identified as a target for HIV. CD32a is an Fcγ receptor known to be expressed on myeloid cells, granulocytes, B cells and NK cells. Little is known about the biology of CD32+CD4+ T cells. Our goal was to understand the dynamics of CD32+CD4+ T cells in tissues. We analyzed these cells in the blood, lymph nodes, spleen, ileum, jejunum and liver of two nonhuman primate models frequently used in biomedical research: African green monkeys (AGM) and macaques. We studied them in healthy animals and during viral (SIV) infection. We performed phenotypic and transcriptomic analysis at different stages of infection. In addition, we compared CD32+CD4+ T cells in tissues with well-controlled (spleen) and not efficiently controlled (jejunum) SIV replication in AGM. The CD32+CD4+ T cells more frequently expressed markers associated with T cell activation and HIV infection (CCR5, PD-1, CXCR5, CXCR3) and had higher levels of actively transcribed SIV RNA than CD32-CD4+T cells. Furthermore, CD32+CD4+ T cells from lymphoid tissues strongly expressed B-cell-related transcriptomic signatures, and displayed B cell markers at the cell surface, including immunoglobulins CD32+CD4+ T cells were rare in healthy animals and blood but increased strongly in tissues with ongoing viral replication. CD32+CD4+ T cell levels in tissues correlated with viremia. Our results suggest that the tissue environment induced by SIV replication drives the accumulation of these unusual cells with enhanced susceptibility to viral infection.

107 Effects of IL-2 and IL-15 on the proliferative and antitumor capacities of allogeneic CD20 CAR-engineered γδ T cells in a 3D B cell lymphoma spheroid assay

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A119-A119
Author(s):  
Lu Bai ◽  
Kevin Nishimoto ◽  
Mustafa Turkoz ◽  
Marissa Herrman ◽  
Jason Romero ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytokine Production ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Car T

BackgroundAutologous chimeric antigen receptor (CAR) T cells have been shown to be efficacious for the treatment of B cell malignancies; however, widespread adoption and application of CAR T cell products still face a number of challenges. To overcome these challenges, Adicet Bio is developing an allogeneic γδ T cell-based CAR T cell platform, which capitalizes on the intrinsic abilities of Vδ1 γδ T cells to recognize and kill transformed cells in an MHC-unrestricted manner, to migrate to epithelial tissues, and to function in hypoxic conditions. To gain a better understanding of the requirements for optimal intratumoral CAR Vδ1 γδ T cell activation, proliferation, and differentiation, we developed a three-dimensional (3D) tumor spheroid assay, in which tumor cells acquire the structural organization of a solid tumor and establish a microenvironment that has oxygen and nutrient gradients. Moreover, through the addition of cytokines and/or tumor stromal cell types, the spheroid microenvironment can be modified to reflect hot or cold tumors. Here, we report on the use of a 3D CD20+ Raji lymphoma spheroid assay to evaluate the effects of IL-2 and IL-15, positive regulators of T cell homeostasis and differentiation, on the proliferative and antitumor capacities of CD20 CAR Vδ1 γδ T cells.MethodsMolecular, phenotypic, and functional profiling were performed to characterize the in vitro dynamics of the intraspheroid CD20 CAR Vδ1 γδ T cell response to target antigen in the presence of IL-2, IL-15, or no added cytokine.ResultsWhen compared to no added cytokine, the addition of IL-2 or IL-15 enhanced CD20 CAR Vδ1 γδ T cell activation, proliferation, survival, and cytokine production in a dose-dependent manner but were only able to alter the kinetics of Raji cell killing at low effector to target ratios. Notably, differential gene expression analysis using NanoString nCounter® Technology confirmed the positive effects of IL-2 or IL-15 on CAR-activated Vδ1 γδ T cells as evidenced by the upregulation of genes involved in activation, cell cycle, mitochondrial biogenesis, cytotoxicity, and cytokine production.ConclusionsTogether, these results not only show that the addition of IL-2 or IL-15 can potentiate CD20 CAR Vδ1 γδ T cell activation, proliferation, survival, and differentiation into antitumor effectors but also highlight the utility of the 3D spheroid assay as a high throughput in vitro method for assessing and predicting CAR Vδ1 γδ T cell activation, proliferation, survival, and differentiation in hot and cold tumors.

scholarly journals High Frequencies of Functional Virus-Specific CD4+ T Cells in SARS-CoV-2 Subjects With Olfactory and Taste Disorders

2021 ◽  
Vol 12 ◽  
Author(s):  
Dalila Mele ◽  
Anna Calastri ◽  
Eugenia Maiorano ◽  
Antonella Cerino ◽  
Michele Sachs ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Control Group ◽  
Presenting Symptoms ◽  
Cell Responses ◽  
Taste Disorders ◽  
Specific Igg

Olfactory and taste disorders (OTD) are commonly found as presenting symptoms of SARS-CoV-2 infection in patients with clinically mild COVID-19. Virus-specific T cells are thought to play an important role in the clearance of SARS-CoV-2; therefore the study of T cell specific immune responses in patients with mild symptoms may help to understand their possible role in protection from severe disease. We evaluated SARS-CoV-2-specific T cell responses to four different peptide megapools covering all SARS-CoV-2 proteins during the acute phase of the disease in 33 individuals with mild or no other symptom beside OTD and in 22 age-matched patients with severe infection. A control group of 15 outpatients with OTD and consistently negative nasopharyngeal SARS-CoV-2 RNA swabs and virus-specific IgG serology was included in the study. Increased frequencies of virus-specific CD4+ and CD8+ T cells were found in SARS-CoV-2 positive patients with OTD compared with those with severe COVID-19 and with SARS-CoV-2 negative OTD individuals. Moreover, enhanced CD4+ and CD8+ T-cell activation induced by SARS-CoV-2 peptides was associated with higher interferon (IFN)γ production. Increased frequencies of Spike (S1/S2)-specific CD4+ T cells showing enhanced IFNγ secretion and granzyme B content were associated with serum spike-specific IgG in the OTD group. In conclusion, patients with SARS-CoV-2 induced OTD develop highly functional virus-specific CD4+ and CD8+ T cells during the symptomatic phase of the disease, suggesting that robust and coordinated T-cell responses provide protection against extension of COVID-19 to the lower respiratory tract.

Abstract 449: Novel Role of Bim in the Regulation of Allogeneic T-Cell Activation and Development of Transplant Vasculopathy

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Anna von Rossum ◽  
Winnie Enns ◽  
Yu P Shi ◽  
Jonathan C Choy
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
T Cell Responses ◽  
Intimal Thickening ◽  
Cell Responses ◽  
Transplant Vasculopathy

Transplant vasculopathy (TV) is an arteriosclerotic disease characterized by intimal thickening of allograft arteries and is a leading cause of heart transplant rejection. T cell responses towards allograft arteries are responsible for the development of TV and understanding the regulatory pathways controlling T cell activation in allograft arteries provides opportunities for the therapeutic attenuation of TV as well as other arteriosclerotic diseases. Bim is a pro-apoptotic Bcl-2 protein known to down-regulate immune responses after viral infections by inducing cell death of effector T cells but its role in regulating allogeneic T cell responses is not known. We compared cell death and alloantigen-driven activation of T cells from Bim +/+ (wild-type), Bim +/- and Bim -/- mice as well as the development of TV in these mice. Bim was required for cell death of both CD4 and CD8 T cells in response to cytokine deprivation in vitro . Unexpectedly, Bim was also required for alloantigen-induced proliferation of both CD4 and CD8 T cells as well as for IL-2 production. When TV was examined in aortic interposition grafts implanted into complete major histocompatibility complex-mismatched mice, intimal thickening was significantly reduced in Bim +/- but not Bim -/- recipients as compared to Bim +/+ counterparts. There was signficantly less CD4 T cell accumulation in the intima of arteries from Bim +/- as compared to Bim +/+ recipients but this effect was not observed in Bim -/- recipients. The accumulation of CD8 T cells in allograft arteries was not affected by differences in Bim expression. Taken together, our data support a novel role for Bim in driving T cell activation in response to allogeneic stimuli and indicate that the effects of this Bcl-2 protein in the pathogenesis of TV likely depends on its dual role in supporting T cell activation and death.

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