scholarly journals IL-2 coordinates IL-2–producing and regulatory T cell interplay

2013 ◽  
Vol 210 (12) ◽  
pp. 2707-2720 ◽  
Author(s):  
Inês F. Amado ◽  
Julien Berges ◽  
Rita J. Luther ◽  
Marie-Pierre Mailhé ◽  
Sylvie Garcia ◽  
...  
Keyword(s):  
T Cell ◽  
Quorum Sensing ◽  
Interleukin 2 ◽  
Cell Subset ◽  
Cd4 T Cell ◽  
Cell Numbers ◽  
Regulatory Circuit ◽  
Reporter Mice ◽  
Lymphocyte Homeostasis

Many species of bacteria use quorum sensing to sense the amount of secreted metabolites and to adapt their growth according to their population density. We asked whether similar mechanisms would operate in lymphocyte homeostasis. We investigated the regulation of the size of interleukin-2 (IL-2)–producing CD4+ T cell (IL-2p) pool using different IL-2 reporter mice. We found that in the absence of either IL-2 or regulatory CD4+ T (T reg) cells, the number of IL-2p cells increases. Administration of IL-2 decreases the number of cells of the IL-2p cell subset and, pertinently, abrogates their ability to produce IL-2 upon in vivo cognate stimulation, while increasing T reg cell numbers. We propose that control of the IL-2p cell numbers occurs via a quorum sensing–like feedback loop where the produced IL-2 is sensed by both the activated CD4+ T cell pool and by T reg cells, which reciprocally regulate cells of the IL-2p cell subset. In conclusion, IL-2 acts as a self-regulatory circuit integrating the homeostasis of activated and T reg cells as CD4+ T cells restrain their growth by monitoring IL-2 levels, thereby preventing uncontrolled responses and autoimmunity.

Loss of EBV-Specific CD4+T Cells during Progression to EBV-Related AIDS Non-Hodgkin Lymphoma: Restoration by Highly Active Antiretroviral Therapy (HAART).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3110-3110
Author(s):  
Erwan R. Piriou ◽  
Christine Jansen ◽  
Karel van Dort ◽  
Iris De Cuyper ◽  
Nening M. Nanlohy ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Cd4 T Cells ◽  
Antigen Processing ◽  
Ex Vivo ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cell Numbers

Abstract Objective: EBV-specific CD8+ T cells have been extensively studied in various settings, and appear to play a major role in the control of EBV-related malignancies. In contrast, it is still unclear whether EBV-specific CD4+ T cells play a role in vivo. To study this question, an assay was developed to measure the CD4+ T-cell response towards two EBV antigens, in both healthy (n=14) and HIV-infected subjects (n=23). In addition, both HAART-treated (n=12) and untreated HIV+ individuals (n=14) - including progressors to EBV-related lymphoma - were studied longitudinally. Methods: EBV-specific CD4+ T cells were stimulated with peptide pools from latent protein EBNA1 and lytic protein BZLF1, and detected by measurement of IFNg-production. Results: After direct ex vivo stimulation, EBNA1 or BZLF1-specific IFNg- (and/or IL2) producing CD4+ T cell numbers were low, and measurable in less than half of the subjects studied (either HIV- and HIV+). Therefore, PBMC were cultured for 12 days in the presence of peptides and IL2 (from day 3), and then restimulated with peptides, allowing specific and reproducible expansion of EBV-specific CD4+ T cells, independent of HLA type and ex vivo antigen processing. Interestingly, numbers of EBV-specific CD4+ T cells inversely correlated with EBV viral load, implying an important role for EBV-specific CD4+ T cells in the control of EBV in vivo. Untreated HIV-infected individuals had a lower CD4+ T cell response to EBNA1 and BZLF1 as compared to healthy EBV carriers and HAART-treated HIV+ subjects. In longitudinal samples, EBNA1-specific, but not BZLF1-specific T-cell numbers increased after HAART, while EBV load was not affected by treatment. In all the progressors to EBV-related lymphoma, EBV-specific CD4+ T cells were lost at least 24 months before lymphoma diagnosis. Conclusions: Both cross-sectional and longitudinal data suggest an important role for EBV-specific CD4+ T cells in the control of EBV-related malignancies. Furthermore, it seems that HAART treatment leads to recovery of EBNA1-specific, but not BZLF1-specific CD4+ T-cell responses, implying changes in the latency pattern of EBV, despite an unaltered cell-associated EBV DNA load. Thus, early HAART treatment might prevent loss of specific CD4+ T-cell help and progression to NHL.

scholarly journals Cathepsin K maintains the number of lymphocytes in vivo

2020 ◽  
Author(s):  
Renate Hausinger ◽  
Marianne Hackl ◽  
Ana Jardon-Alvarez ◽  
Miriam Kehr ◽  
Sandra Romero Marquez ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cathepsin K ◽  
Hematopoietic Stem ◽  
Cell Numbers ◽  
Cell Compartments ◽  
Lymphocyte Homeostasis

AbstractIn this study, we investigated the influence of the loss of Cathepsin K (Ctsk) gene on the hematopoietic system in vitro and in vivo. We found that cultures with Lineage- SCA1+ KIT+ (LSK) cells on Ctsk deficient stromal cells display reduced colony formation and proliferation, with increased differentiation, giving rise to repopulating cells with reduced ability to repopulate the donor LSK and T cell compartments in the bone marrow. Subsequent in vivo experiments showed impairment of lymphocyte numbers, but, gross effects on early hematopoiesis or myelopoiesis were not found. Most consistently in in vivo experimental settings, we found a significant reduction of (donor) T cell numbers in the bone marrow. Lymphocyte deregulation is also found in transplantation experiments, which revealed that Ctsk is required for optimal regeneration not only of T cells, but also of B cells. Interestingly, cell non-autonomous Ctsk regulates both B- and T cell numbers, but T cell numbers in the bone marrow require an additional autonomous Ctsk-dependent process. Thus, we show that Ctsk is required for the maintenance of hematopoietic stem cells in vitro, but in vivo, Ctsk deficiency most strongly affects lymphocyte homeostasis, particularly of T cells in the bone marrow.

scholarly journals Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential.

1993 ◽  
Vol 177 (3) ◽  
pp. 627-636 ◽  
Author(s):  
D Fowell ◽  
D Mason
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Autoimmune Diabetes ◽  
Interleukin 2 ◽  
Cell Subset ◽  
Cd4 T Cell ◽  
Male Rats ◽  
Cell Repertoire ◽  
T Cell Subset

Diabetes was induced in a normal nonautoimmune rat strain by rendering the animals relatively T cell deficient using a protocol of adult thymectomy and sublethal gamma irradiation. All male rats and 70% of females developed an acute syndrome with severe loss of weight and hyperglycemia. Diabetes in these lymphopoenic rats was associated with extensive insulitis involving CD4+ and CD8+ T cells and macrophages. The CD8+ T cells were essential for the development of diabetes but not insulitis. The autoimmune diabetes and insulitis were completely prevented by the injection of a particular CD4+ T cell subset, isolated from healthy syngeneic donors, of the phenotype CD45RClow T cell receptor alpha/beta+ RT6+ Thy-1- OX-40-. Cells of this protective phenotype, which make up about 5% of thoracic duct lymphocytes, were found to provide help for secondary antibody responses and produce interleukin 2 (IL-2) and IL-4, but no interferon gamma, on in vitro activation. These data provide evidence for the presence of autoreactive T cells in the normal immune system of the rat and reveal that in the intact animal these cells are prevented from expressing their autoreactive potential by other T cells.

scholarly journals Rasgrp1 mutation increases naïve T-cell CD44 expression and drives mTOR-dependent accumulation of Helios+ T cells and autoantibodies

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Stephen R Daley ◽  
Kristen M Coakley ◽  
Daniel Y Hu ◽  
Katrina L Randall ◽  
Craig N Jenne ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Subset ◽  
Missense Variant ◽  
Cd4 T Cell ◽  
Nucleotide Exchange ◽  
Cd44 Expression ◽  
Nucleotide Exchange Factor

Missense variants are a major source of human genetic variation. Here we analyze a new mouse missense variant, Rasgrp1Anaef, with an ENU-mutated EF hand in the Rasgrp1 Ras guanine nucleotide exchange factor. Rasgrp1Anaef mice exhibit anti-nuclear autoantibodies and gradually accumulate a CD44hi Helios+ PD-1+ CD4+ T cell population that is dependent on B cells. Despite reduced Rasgrp1-Ras-ERK activation in vitro, thymocyte selection in Rasgrp1Anaef is mostly normal in vivo, although CD44 is overexpressed on naïve thymocytes and T cells in a T-cell-autonomous manner. We identify CD44 expression as a sensitive reporter of tonic mTOR-S6 kinase signaling through a novel mouse strain, chino, with a reduction-of-function mutation in Mtor. Elevated tonic mTOR-S6 signaling occurs in Rasgrp1Anaef naïve CD4+ T cells. CD44 expression, CD4+ T cell subset ratios and serum autoantibodies all returned to normal in Rasgrp1AnaefMtorchino double-mutant mice, demonstrating that increased mTOR activity is essential for the Rasgrp1Anaef T cell dysregulation.

scholarly journals MHC control of CD4+ T cell subset activation.

1989 ◽  
Vol 170 (6) ◽  
pp. 2135-2140 ◽  
Author(s):  
J S Murray ◽  
J Madri ◽  
J Tite ◽  
S R Carding ◽  
K Bottomly
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Cell Subset ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Selective Activation ◽  
Ifn Gamma

The present results demonstrate that CD4+ T cells activated in the primary in vivo response to antigen produce distinct patterns of cytokines depending upon the MHC class II haplotype of the responding mice. I-As mice were found to selectively activate IL-2/IFN-gamma-producing CD4+ T cells, whereas I-Ab mice exhibited selective activation of IL-4-producing CD4+ T cells in response to collagen IV. The effector response phenotype was found to correlate with the cytokine phenotype of CD4+ T cells activated in vivo; IL-2/IFN-gamma-producing cells giving rise to proliferative (cell-mediated) responses, IL-4-producing cells leading to secondary IgG (humoral) responses. Together the data support the notion that the outcome of a given immune response (e.g., protection vs. onset, tolerance vs. autoimmunity) may be determined in part by the type of CD4+ T cells initially activated by antigen. Moreover, the present experiments demonstrate for the first time that polymorphism in class II MHC can determine such selective activation of different cytokine-producing CD4+ T cell phenotypes.

In vivo CD4+ T-cell up-regulation and high dose side effects of refolded duck interleukin-2

Cytokine ◽  
2006 ◽  
Vol 34 (5-6) ◽  
pp. 297-302 ◽  
Author(s):  
Jinyong Wang ◽  
Jing Qi ◽  
Huigang Shen ◽  
Jiyong Zhou ◽  
Jie Fang ◽  
...  
Keyword(s):  
T Cell ◽  
Side Effects ◽  
Interleukin 2 ◽  
Cd4 T Cell ◽  
High Dose

scholarly journals Pretransplant detection of human minor histocompatibility antigen- specific naive and memory interleukin-2-secreting T cells within class I major histocompatibility complex (MHC)-restricted CD8+ and class II MHC-restricted CD4+ T-cell subsets

Blood ◽  
1993 ◽  
Vol 82 (1) ◽  
pp. 298-306 ◽  
Author(s):  
M Theobald ◽  
D Bunjes
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Interleukin 2 ◽  
Cell Subset ◽  
T Cell Subsets ◽  
Graft Versus Host ◽  
T Cell Subset ◽  
Histocompatibility Complex

Recent studies have shown that host-reactive interleukin-2 (IL-2)- secreting donor T lymphocytes (TI) are critically involved in the development of acute graft-versus-host disease (GVHD) after allogeneic HLA-identical sibling bone marrow transplantation (BMT). To further characterize the responding TI, we determined the frequency of pretransplant IL-2-secreting TI-precursors (TI-p) between eight HLA-A, - B, -C, -DR, and -DQ-identical sibling donor-host pairs in both the graft-versus-host (GVH) and the host-versus-graft (HVG) direction. High frequencies of pretransplant host-reactive donor TI-p (1/18,000 to 1/49,000) were detectable in five patients with grade II acute GVHD. Donor-reactive host TI-p (1/3,700 to 1/31,000) were observed in previously in vivo primed (n = 5) and unprimed (n = 1) patients. In two pairs tested after previous in vivo priming, pretransplant donor- reactive host TI-p were highly enriched within the CD45RO+ memory T- cell subset. Previously unprimed host-reactive donor TI-p occurred in almost equal frequencies within CD45RO+ and CD45RO- T cells. Both CD4+ and CD8+ T-cell subsets contributed in comparable frequencies to host- and donor-reactive TI-p. Recognition of minor histocompatibility (mH) antigens by CD8+ TI-p appeared to be class I major histocompatibility complex (MHC)-restricted, whereas CD4+ TI-p operated in a class II (HLA- DR) MHC-restricted fashion. Even between oligonucleotide-defined HLA- DPB1-disparate sibling donor-host pairs (n = 3), either responding T- cell subset was found to recognize cellularly defined mH antigens. These data indicate that various T-cell subsets contribute to host- and donor-reactive IL-2-secreting TI in allogeneic sibling BMT.

scholarly journals Levels of Cytokines and Immune Activation Markers in Plasma in Human Immunodeficiency Virus Infection: Quality Control Procedures

1998 ◽  
Vol 5 (6) ◽  
pp. 755-761 ◽  
Author(s):  
Najib Aziz ◽  
Parunag Nishanian ◽  
John L. Fahey
Keyword(s):  
Human Immunodeficiency Virus ◽  
Quality Control ◽  
T Cell ◽  
Interleukin 2 ◽  
Cd4 T Cell ◽  
Reference Ranges ◽  
Activation Markers ◽  
Cell Numbers ◽  
Tnf Α ◽  
Immunodeficiency Virus

ABSTRACT Procedures for quality control (QC) in a laboratory that concentrates on cytokine and soluble marker measurements in biological fluids are outlined. Intra-assay, interassay, and interlaboratory experiences are presented. Plasma and serum β2-microglobulin (β2M) and neopterin test data are presented in greatest detail, along with substantial tumor necrosis factor alpha (TNF-α), gamma interferon, soluble interleukin-2 receptor-α (sIL-2Rα), sTNF-RII, IL-4, and IL-6 data. Recommended QC procedures for cytokine and soluble-marker testing include replicate testing of two or more reference samples provided by the kit manufacturer, replicate testing of in-house frozen reference QC samples that represent normal and abnormal analyte contents, retesting 15 to 20% of randomly selected samples, and comparing normal reference ranges each year. Also, eight cytokines and soluble markers were evaluated in human immunodeficiency virus (HIV)-seronegative and HIV-seropositive individuals stratified on the basis of CD4 T-cell numbers. Levels of some but not all cytokines in serum increased in HIV infection. There was a tendency for cytokines to increase with more advanced disease, defined by reduced CD4 T-cell numbers. Cytokine changes did not relate closely to CD4 level, indicating that separate information was provided by the measurements of TNF-α, sTNF-RII, sIL-2Rα, β2M, and neopterin. Serum IL-4 and TNF-α levels were not increased. The quality of laboratory data can impact on clinical relevance. Interlaboratory comparisons revealed substantial differences at some sites and documented the need for external proficiency-testing quality assurance programs.

Induction of CD4+/CD25+ regulatory T cells by targeting of antigens to immature dendritic cells

Blood ◽  
2003 ◽  
Vol 101 (12) ◽  
pp. 4862-4869 ◽  
Author(s):  
Karsten Mahnke ◽  
Yingjie Qian ◽  
Jürgen Knop ◽  
Alexander H. Enk
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Interleukin 2 ◽  
Cd4 T Cell ◽  
Allergic Reactions ◽  
Phenotypic Analysis ◽  
Immature Dendritic Cells

AbstractCoupling of ovalbumin (OVA) to anti–DEC-205 monoclonal antibody (mAb) (αDEC) induced the proliferation of OVA-specific T cells in vivo. Expansion was short-lived, caused by dendritic cells (DCs), and rendered T cells anergic thereafter. Phenotypic analysis revealed the induction of CD25+/CTLA-4+ T cells suppressing proliferation and interleukin-2 (IL-2) production of effector CD4+ T cells. The findings were supported by 2 disease models: (1) CD4+ T-cell–mediated hypersensitivity reactions were suppressed by the injection of αDEC-OVA and (2) the application of hapten-coupled αDEC-205 reduced CD8+ T-cell–mediated allergic reactions. Thus, targeting of antigens to immature DCs through αDEC antibodies led to the induction of regulatory T cells, providing the basis for novel strategies to induce regulatory T cells in vivo.

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