scholarly journals IL-7 and IL-15 combined with strong TCR stimulation decrease Treg suppressive activity in healthy donors and patients with rheumatoid arthritis

2020 ◽  
Author(s):  
Daniil Shevyrev ◽  
Valeriy Tereshchenko ◽  
Alexey Sizikov ◽  
Vladimir Kozlov
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
Autoimmune Diseases ◽  
Homeostatic Proliferation ◽  
Suppressive Activity ◽  
Cd8 Cells ◽  
Cell Clones ◽  
Healthy Donors ◽  
Tcr Signals ◽  
And Function

Homeostatic proliferation (HP) is a physiological process to reconstitute the T-cell pool after lymphopenia with IL-7 and IL-15 being the key cytokines regulating the process. However, there is no evidence whether these cytokines influence the function of regulatory T cells (Tregs). Since lymphopenia often accompanies autoimmune diseases, we decided to study the proliferation rate and function of Tregs stimulated by IL-7 and IL-15 in patients with rheumatoid arthritis (RA) compared to healthy donors (HD). The study used peripheral blood from 14 RA patients and 18 HD. Proliferation of purified CD3CD4CD25CD127 cells was assessed by flow cytometry using CFSE. Tregs were stimulated by anti-CD3, IL-7, IL-15, IL-7, or IL-15 combined with anti-CD3, and by IL-2+anti-CD3, and their functional activity was evaluated in each case by CD4 and CD8 cells proliferation inhibition. The suppressive activity of peripheral Tregs did not differ between RA and HD; however, it significantly decreased when IL-7 or IL-15 were applied together with strong TCR stimulation with anti-CD3 antibodies. Herewith Treg proliferation caused by IL-7 and IL-15 was lower in RA than in HD. The revealed decrease in Treg suppressive activity can lead to the proliferation of potentially self-reactive T-cell clones, which can receive relatively strong TCR signals. This may be another explanation of why lymphopenia is associated with the development of autoimmune diseases. The revealed decrease of Treg proliferation under IL-7 and IL-15 may lead to a delay in Treg pool reconstitution in patients with rheumatoid arthritis.

scholarly journals Regulatory T Cells Fail to Suppress Fast Homeostatic Proliferation In Vitro

Life ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 245
Author(s):  
Daniil Shevyrev ◽  
Valeriy Tereshchenko ◽  
Elena Blinova ◽  
Nadezda Knauer ◽  
Ekaterina Pashkina ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Autoimmune Diseases ◽  
Peripheral Blood ◽  
Treg Cells ◽  
Homeostatic Proliferation ◽  
Suppressive Activity ◽  
Healthy Donors

Homeostatic proliferation (HP) is a physiological process that reconstitutes the T cell pool after lymphopenia involving Interleukin-7 and 15 (IL-7 and IL-15), which are the key cytokines regulating the process. However, there is no evidence that these cytokines influence the function of regulatory T cells (Tregs). Since lymphopenia often accompanies autoimmune diseases, we decided to study the functional activity of Tregs stimulated by HP cytokines from patients with rheumatoid arthritis as compared with that of those from healthy donors. Since T cell receptor (TCR) signal strength determines the intensity of HP, we imitated slow HP using IL-7 or IL-15 and fast HP using a combination of IL-7 or IL-15 with anti-CD3 antibodies, cultivating Treg cells with peripheral blood mononuclear cells (PBMCs) at a 1:1 ratio. We used peripheral blood from 14 patients with rheumatoid arthritis and 18 healthy volunteers. We also used anti-CD3 and anti-CD3 + IL-2 stimulation as controls. The suppressive activity of Treg cells was evaluated in each case by the inhibition of the proliferation of CD4+ and CD8+ cells. The phenotype and proliferation of purified CD3+CD4+CD25+CD127lo cells were assessed by flow cytometry. The suppressive activity of the total pool of Tregs did not differ between the rheumatoid arthritis and healthy donors; however, it significantly decreased in conditions close to fast HP when the influence of HP cytokines was accompanied by anti-CD3 stimulation. The Treg proliferation caused by HP cytokines was lower in the rheumatoid arthritis (RA) patients than in the healthy individuals. The revealed decrease in Treg suppressive activity could impact the TCR landscape during lymphopenia and lead to the proliferation of potentially self-reactive T cell clones that are able to receive relatively strong TCR signals. This may be another explanation as to why lymphopenia is associated with the development of autoimmune diseases. The revealed decrease in Treg proliferation under IL-7 and IL-15 exposure can lead to a delay in Treg pool reconstitution in patients with rheumatoid arthritis in the case of lymphopenia.

Pathologic Clonal CTLResponses - Non Random Nature of the TCR Restriction in LGL Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3241-3241
Author(s):  
Marcin W. Wlodarski ◽  
Christine O’Keefe ◽  
Evan Howe ◽  
Alexander Rodriquez ◽  
Thomas Loughran ◽  
...  
Keyword(s):  
T Cell ◽  
Autoimmune Response ◽  
Therapeutic Modality ◽  
T Cell Clones ◽  
Cd8 Cells ◽  
Cell Clones ◽  
Healthy Donors ◽  
A Minor ◽  
Random Nature ◽  
Lgl Leukemia

Abstract T-LGL leukemia, a clonal lymphoproliferation of CTL associated with cytopenias, seems to be triggered/sustained by antigenic drive. It is likely that hematopoietic progenitors are the targets in this process. We hypothesized that CTL clones evolve not randomly but in the context of an autoimmune response. We studied 75 patients with suspected LGL leukemia. The detection strategy for signature clonotypes included VB flow cytometric typing and VB specific PCR or multiplex PCR on cDNA from sorted CD8+ cells, followed by colony sequencing of the VB CDR3 regions (clonotypes). In 60 patients, we were able to isolate and characterize 86 pathologically expanded clonotypes (in 22 patients >1 immunodominant clone was detected); in most of the cases, the over-represented VB families nominally were >20% of all CD8+ cells. Clonal frequency was 65%± 30% of a given VB family or 35.4%± 31% of the total CD8+ population. By comparison, the most expanded clones in controls constitute to only 0.7% of the CD8+ repertoire. Two patients showed an identical immunodominant clonotype also shared with a third patient in whom it was not expanded. We also found sequence identity between an immunodominant and a minor clonotype and between 2 minor clonotypes in 2 LGL patient pairs. In 2 other patient pairs, a major clonotype showed a striking homology to a minor clonotype. Not only were identical clonotypes shared between the patients, a high degree of similarity was found between a large number of minor clonotypes. Likely, these minor clonotypes are the remnants of the initial polyclonal response. When up to 172 clones were sequenced per VB family in 24 healthy donors, only one shared clonotype was found in 2 donors and only a total of 11 sequences were detected to show the level of homology as detected in LGL. Immunodominant clonotypes can be used as tumor markers or to study expansion of LGL clones in correlation with disease activity. Identification of pathologic clonotypes allowed for design of a clonotype-specific real time PCR that allowed for monitoring of the clonal behavior over the time. For 7 patients followed serially either by sequencing or clonotype-specific Taq-Man PCR, a marked decrease in the frequency of the immunodominant clone was observed with successful therapy. This process resulted in increased clonal diversity and decreased redundancy. Some clonotypes that appeared post therapy showed sequence similarity to the original immunodominant clones. Given the normally immense variability of the TCR repertoire and the very low frequency of shared clonotypes identified in healthy donors, our findings suggest a non-random nature of LGL transformation. This possibly occurred in the context of initially polyclonal immune response directed against common antigenic target. Clonotypic sequences may be used to monitor the frequency of malignant T cell clones, but such an approach may also be applied for polyclonal responses in which clonotypes derived from most significantly expanded T cell clones may serve as marker for specific autoimmune processes. Finally, the availability of the clonotypic sequences may allow for measurements of anti-idiotypic responses and study of the applicability of clonotype-based anti-idiotypic vaccination as a potential therapeutic modality for T cell malignancies.

Study of CTLA-4 Regulation in Large Granular Lymphocyte Leukemia Cells and Their Normal Counterparts.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3871-3871
Author(s):  
Marcin W. Wlodarski ◽  
Megan Quimper ◽  
Lukasz Gondek ◽  
Alexander Rodriquez ◽  
Jaroslaw P. Maciejewski
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
Autoimmune Diseases ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Large Granular Lymphocyte ◽  
Snp Analysis ◽  
Cd8 Cells ◽  
Cell Responses

Abstract T cell large granular lymphocyte (T-LGL) leukemia is a clonal lymphoproliferation of terminal cytotoxic T cells. T-LGL differs from other lymphoid malignancies as it is not entirely autonomous but appears to be sustained by a persistent antigenic drive. The antigen driven process may be suspected based on the frequent association of T-LGL with autoimmune conditions such as autoimmune neutropenia or rheumatoid arthritis. In these diseases, the LGL clone may be a part of an initially polyclonal immune response. CTLA-4 (CD152) is an accessory molecule expressed on CD4+ and some CD8+ cells involved in the regulation of T cell responses; upon triggering by one of its ligands (B7, CD28) CTLA-4 decreases T-cell activation and proliferation and contributes to the termination of antigenic responses. Knockout CTLA-4 mice develop autoimmune symptoms and a lymphoproliferative syndrome. Clinically, CTLA-4 was implicated in the induction of allo-tolerance and in the pathophysiologic mechanisms leading to autoimmune diseases such as thyroditis and rheumatoid arthritis. In addition, polymorphisms within CTLA-4 promoter and exon I have been recognized as immunogenetic predisposition factors for a variety of autoimmune diseases. Some experimental observations suggest defective regulation of the LGL clone and various intra- and extra-cellular mechanisms were implicated. Based on the biologic properties of CTLA4, we designed our experiments to test the potential role of CTLA-4 in dysregulation of clonal T cell responses in T-LGL. Decreased expression and impaired functional activity may be a result of a genetic predisposition due to known CTLA4 promoter and exon I polymorphism, 28 LGL patients were studied using SNP analysis. We have found for the +49 A/G polymorphism in exon I that 42% of LGL patients were homozygous while 38% and 20% were heterozygous for A/G exchange and homozygous for G, respectively. However, this result was comparable to large cohorts of controls reported in various publications and controls (N=18) studied in our laboratory. No patients with CTLA-4 promoter polymorphisms (-658C>T, -319C>T) were found in the LGL cohort. Using intracellular staining and flow cytometry we studied induced and steady state expression of CD152 in LGL cells. As compared to controls (N=14) in whom PMA/Ionomycin and PHA treatment resulted in an up-modulation of the CD152 expression in CD8+ cells (3.2+/− 3.4% vs. 17+/− 6.8% upon stimulation), the inducibility of CTLA-4 was decreased in CD8+ cells derived from patients with LGL (N=11; 3.7+/− 3.5% vs. 8.2+/− 7.5% upon stimulation). Stimulation appeared to be adequate as indicated by comparable CD69 upregulation. As LGL cells phenotypically correspond to mature effector CTL, we investigated whether impaired CTLA-4 induction is rather a feature of normal mature CTL effectors rather than a defect of LGL clone. Following stimulation, we have differentially stained CD8+CD57+ and CD8+CD57− cells from controls and determined expression of CD152; mature CD57+CD8 positive cells failed to express CTLA4 upon stimulation. In analogy, similar procedure was applied to patients with LGL: normal polyclonal CD8+CD57− cells showed induction of CTLA-4 while LGL cells were refractory. These results suggest that the survival and activation of terminal effector CTL including LGL cells are not regulated by CTLA-4 expression.

scholarly journals Antigen-specific T lymphocyte clones. I. Characterization of a T lymphocyte clone expressing antigen-specific suppressive activity.

1981 ◽  
Vol 153 (5) ◽  
pp. 1246-1259 ◽  
Author(s):  
M Fresno ◽  
G Nabel ◽  
L McVay-Boudreau ◽  
H Furthmayer ◽  
H Cantor
Keyword(s):  
T Cell ◽  
T Lymphocyte ◽  
Antigen Binding ◽  
Suppressive Activity ◽  
Cell Functions ◽  
Cell Clones ◽  
Helper Activity ◽  
Binding Peptides ◽  
Lymphocyte Clone

We have generated continuously propagatable T lymphocyte clones to study antigen-specific T cell functions. All Ly-2+ clones mediate suppressive activity and secrete a characteristic pattern of polypeptides that differs from Ly-2- T cell clones. Cells of one clone, Cl.Ly23/4, specifically bind glycophorin from sheep erythrocytes (SRBC). After incubation with [35S]methionine, supernate material from this clone also contains biosynthetically labeled 70,000-mol wt proteins that specifically bind to SRBC and this binding is inhibited by glycophorin from sheep but not other erythrocytes. These antigen-binding 70,000-mol wt peptides specifically and completely suppress primary anti-SRBC responses generated by mixtures of primed Ly-1+2- cells and B cells. Suppression by these antigen-binding peptides reflects direct inhibition of T-helper activity.

Markers of Responsiveness to ATG/CsA Therapy in Patients with Severe Aplastic Anemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1699-1699
Author(s):  
Abdo S. Haddad ◽  
Ania Jankowska ◽  
Theodore Ghazal ◽  
Sandra Smieszek ◽  
Ramon Tiu ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Overall Response Rate ◽  
Response Rate ◽  
First Line ◽  
Cd8 Cells ◽  
Overall Response ◽  
Flow Cytometric ◽  
Cell Clones ◽  
Immune Mediated

Abstract While ATG/CsA therapy results in a significant response rate in severe aplastic anemia (sAA), a substantial minority of patient remains refractory. Lack of response to intense immunosuppression (IS) may be a consequence of “non -immune” pathogenesis or be due inadequate intensity/duration of IS or exhaustion of stem cell reserves. Identification of markers of IS responsiveness would allow for a better patient selection and early application of stem cell transplantation (SCT). Various parameters of immune activation have been investigated but suitable makers of responsiveness to IS were not identified. Previously, we have shown a potential utility of flow cytometric analysis of T cell VB repertoire to identify expanded T cell clones that are involved in the autoimmune attack on hematopoietic progenitor and stem cells in immune-mediated bone marrow failure. Among 110 AA cases treated in our institution, 88 had sAA; 12 of them underwent early SCT while 74 were initially treated ATG/CsA. Of those patients, 60 received equine ATG (H-ATG) as a primary (N=56), or salvage modality (N=4) after rabbit ATG (R-ATG) with overall response rate (defined by transfusion independence and not fulfilling severity criteria) of 65% (66% as a first line). R-ATG was used in 23 patients as an initial (N=15) or salvage treatment (N=7) with overall response rate of 60% (61% as a first line, P=.88 as compared to H-ATG). For 24 patients (3 with mAA) we performed serial flow cytometric VB utilization profiling within CD3 CD4 and CD8 cells. All of these patients were minimally transfused and not infected at the time of initial testing. Prior to therapy, VB expansions (≥2 VB families) within CD4 and CD8 cells (defined as >mean+2xSD value for a given VB family in controls) indicative of the presence of potentially pathogenic T cell clones were present in 7/21 and 13/21 patients, respectively, P=.26. Nominally, CD4 and CD8 VB overrepresentations were 7% >mean+2xSD (1.7%-17.3%) and 9.26% (1.8%-24.5%), respectively. Within this specific sub-cohort of patients, the overall response rate measured at 6 months was 14/19 (73%). Response correlated with the presence of VB expansions prior to therapy; responders showed on average more and larger CD8 expansions (2 VB/patient, 0–3; 6.16% av. size, 1.8%-24.5%) and larger expansions vs. lower number of and smaller CD8 expansions (0.6 VB/patient, 0–3; 1.7% av. size, 5.7–11.4%) were seen in refractory patients (only 1/5 refractory patients had VB expansions). Conversely, 10/14 (71%) responses were seen in patients in with ≥2 CD8 VB expansion, only 1 patient responded but had no CD8 VB expansions. In contrast, only 1/5 (20%) ≥2 CD8 VB expansion were seen in refractory patients. Remarkably, hematologic improvement was associated with resolution of at least one significant VB expansion during monthly evaluations. In patients who relapsed reappearance of the original or new VB expansion within CD8 cells was seen. We conclude that CD8 VB expansions involving ≥2 VB families may predict of subsequent response to IS suggesting that VB typing may be a suitable monitoring tool for patients with immune-mediated AA.

Activation by Estrogen of the Number and Function of Forbidden T-Cell Clones in Intermediate T-Cell Receptor Cells

1996 ◽  
Vol 172 (2) ◽  
pp. 163-171 ◽  
Author(s):  
Mauro Nakayama ◽  
Kazuo Otsuka ◽  
Kazunari Sato ◽  
Katsuhiko Hasegawa ◽  
Yasser Osman ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Clones ◽  
Receptor Cells ◽  
Cell Clones ◽  
And Function

Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 758-765 ◽  
Author(s):  
Jagadeesh Bayry ◽  
Sébastien Lacroix-Desmazes ◽  
Cedric Carbonneil ◽  
Namita Misra ◽  
Vladimira Donkova ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Autoimmune Diseases ◽  
Intravenous Immunoglobulin ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Activity ◽  
Interleukin 12 ◽  
Immune Mediated ◽  
And Function

Normal immunoglobulin G for therapeutic use (intravenous immunoglobulin [IVIg]) is used in an increasing number of immune-mediated conditions, including acute and chronic/relapsing autoimmune diseases, transplantation, and systemic inflammatory disorders. Several mutually nonexclusive mechanisms of action account for the immunoregulatory effects of IVIg. Although IVIg inhibits T-cell proliferation and T-cell cytokine production, it is unclear whether these effects are directly dependent on the effects of IVIg on T cells or they are dependent through the inhibition of antigen-presenting cell activity. Here, we examined the effects of IVIg on differentiation, maturation, and function of dendritic cells (DCs). We show that IVIg inhibits the differentiation and maturation of DCs in vitro and abrogates the capacity of mature DC to secrete interleukin-12 (IL-12) on activation while enhancing IL-10 production. IVIg-induced down-regulation of costimulatory molecules associated with modulation of cytokine secretion resulted in the inhibition of autoreactive and alloreactive T-cell activation and proliferation. Modulation of DC maturation and function by IVIg is of potential relevance to its immunomodulatory effects in controlling specific immune responses in autoimmune diseases, transplantation, and other immune-mediated conditions.

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