scholarly journals T-cell and antibody immunity after COVID-19 mRNA vaccines in healthy and immunocompromised subjects-An exploratory study.

2021 ◽  
Author(s):  
Rakesh Sindhi ◽  
Chethan Ashokkumar ◽  
Brianna Spishock ◽  
Maggie Saunders ◽  
Angelo Mabasa ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Healthy Subjects ◽  
Vaccine Dose ◽  
Suppressor Cells ◽  
Cd8 Cells ◽  
Hla Dr ◽  
Before And After ◽  
Serial Samples ◽  
Spike Sequence

Background: In recent studies, up to half of immunocompromised (IC) subject populations fail to develop antibodies after COVID-19 vaccination. Purpose and Methods: Here, we explore whether T-cells which respond to the spike (S) antigenic sequence and its less conserved S1, and the conserved S2 component are present in serial samples before and after each dose of mRNA1273 or BNT162b2 vaccines in 20 healthy immunocompetent subjects. Single samples from 7 vaccinated IC subjects were also tested. Simultaneously, we measured IgG antibodies to the receptor binding domain (RBD) of S1, and anti-S IgG, and frequencies of monocytic CD14+HLA-DR- (M-MDSC) and polymorphonuclear CD14-CD15+CD11b+ (PMN-MDSC) myeloid-derived suppressor cells. Results: In healthy subjects, S1-, S2-, and S-reactive CD4 and CD8 T-cell frequencies showed a numeric but not statistically significant decrease after the first vaccine dose and were accompanied by increased MDSC frequencies (p<0.05). After the second dose, S2- and S-reactive CD4 and CD8 cells and MDSC approached pre-vaccination levels. In healthy subjects, a) S1-reactive CD8 frequencies were significantly higher after the second dose compared with pre-vaccination levels (p=0.015), b) anti-RBD and anti-S IgG were present in all after the second dose. Among seven IC subjects, anti-RBD and anti-S IgG were absent in 4 and 3 subjects, respectively. S1-reactive CD8 cells were identified in 2 of 4 anti-RBD negative subjects. S-reactive CD4 or CD8 cells were identified in all three anti-S negative subjects. Conclusions: In healthy immunocompetent subjects, mRNA vaccines induce antibodies to the spike antigenic sequences and augment CD8 cells reactive to the S1 spike sequence, which is more specific for the SARS-CoV-2 virus. In this exploratory cohort of vaccinated immunocompromised subjects, S1-reactive CD8 cells can be detected in some who are negative for RBD antibody, and S-reactive T-cells are present in all who are negative for spike antibody.

scholarly journals T-cell activation and subset patterns are altered in B-CLL and correlate with the stage of the disease

Blood ◽  
1989 ◽  
Vol 74 (2) ◽  
pp. 786-792 ◽  
Author(s):  
TH Totterman ◽  
M Carlsson ◽  
B Simonsson ◽  
M Bengtsson ◽  
K Nilsson
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Healthy Subjects ◽  
Lymphocytic Leukemia ◽  
Stage Ii ◽  
T Cell Subsets ◽  
Cd8 Cells ◽  
Hla Dr ◽  
The Absolute

Abstract Two-color FACS analysis was used to study activated and “functional” T and natural killer (NK) cell subsets of circulating lymphocytes in 23 patients with B-type chronic lymphocytic leukemia (B-CLL) and in 30 healthy subjects. As compared with controls, B-CLL patients had increased absolute numbers of phenotypically activated, HLA-DR+ CD4+ and CD8+ cells and T suppressor/effector (CD11b+CD8+) cells. When patients in Rai stages II through IV (n = 11) were compared with cases in Rai stages O through I (n = 12), the former group of patients had higher numbers of activated CD4+ and CD8+ T cells and decreased levels of suppressor/effector T cells. The absolute numbers of T suppressor/inducer (CD45R+CD4+) cells were elevated in patients with stage O through I disease but within normal range in stage II through IV leukemia. We further showed that the absolute numbers of NK-like (CD16+) cells and their activated counterparts (DR+CD16+) are elevated in B-CLL patients as compared with healthy subjects. The comparison of relative T and NK subsets in the blood of patients and controls showed that the proportions of CD4+, CD8+, and CD16+ cells expressing the activation marker HLA-DR were increased in B-CLL. Furthermore, the percentage of T-suppressor/inducer (CD45R+) cells within the CD4+ population was decreased in the patients. The proportion of T- suppressor/effector (CD11b+) cells within the CD8+ subset was reduced in subjects with stage II-IV disease only. When stimulated in vitro with the T-cell-dependent inducer TPA, B-CLL cells from patients in Rai stages II through IV secreted larger amounts of IgM as compared with cells from stage O through I patients. A positive correlation was observed between the degree of phenotypic activation of CD4+ T-helper cells and their functional capacity to augment IgM secretion by autologous B-CLL cells. Our findings indicate a tumor cell-directed regulatory role of T cells (and possibly NK cells as well) in B-CLL. Furthermore, monitoring of phenotypically activated and functional T- cell subsets may be helpful in the prediction of disease progression and timing of therapy in B-CLL.

scholarly journals T-cell activation and subset patterns are altered in B-CLL and correlate with the stage of the disease

Blood ◽  
1989 ◽  
Vol 74 (2) ◽  
pp. 786-792 ◽  
Author(s):  
TH Totterman ◽  
M Carlsson ◽  
B Simonsson ◽  
M Bengtsson ◽  
K Nilsson
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Healthy Subjects ◽  
Lymphocytic Leukemia ◽  
Stage Ii ◽  
T Cell Subsets ◽  
Cd8 Cells ◽  
Hla Dr ◽  
The Absolute

Two-color FACS analysis was used to study activated and “functional” T and natural killer (NK) cell subsets of circulating lymphocytes in 23 patients with B-type chronic lymphocytic leukemia (B-CLL) and in 30 healthy subjects. As compared with controls, B-CLL patients had increased absolute numbers of phenotypically activated, HLA-DR+ CD4+ and CD8+ cells and T suppressor/effector (CD11b+CD8+) cells. When patients in Rai stages II through IV (n = 11) were compared with cases in Rai stages O through I (n = 12), the former group of patients had higher numbers of activated CD4+ and CD8+ T cells and decreased levels of suppressor/effector T cells. The absolute numbers of T suppressor/inducer (CD45R+CD4+) cells were elevated in patients with stage O through I disease but within normal range in stage II through IV leukemia. We further showed that the absolute numbers of NK-like (CD16+) cells and their activated counterparts (DR+CD16+) are elevated in B-CLL patients as compared with healthy subjects. The comparison of relative T and NK subsets in the blood of patients and controls showed that the proportions of CD4+, CD8+, and CD16+ cells expressing the activation marker HLA-DR were increased in B-CLL. Furthermore, the percentage of T-suppressor/inducer (CD45R+) cells within the CD4+ population was decreased in the patients. The proportion of T- suppressor/effector (CD11b+) cells within the CD8+ subset was reduced in subjects with stage II-IV disease only. When stimulated in vitro with the T-cell-dependent inducer TPA, B-CLL cells from patients in Rai stages II through IV secreted larger amounts of IgM as compared with cells from stage O through I patients. A positive correlation was observed between the degree of phenotypic activation of CD4+ T-helper cells and their functional capacity to augment IgM secretion by autologous B-CLL cells. Our findings indicate a tumor cell-directed regulatory role of T cells (and possibly NK cells as well) in B-CLL. Furthermore, monitoring of phenotypically activated and functional T- cell subsets may be helpful in the prediction of disease progression and timing of therapy in B-CLL.

scholarly journals Cyclophosphamide Exerts Significant Immunomodulatory Function in Myeloma Patients Treated with Pomalidomide and Dexamethasone

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4482-4482 ◽  
Author(s):  
James Croft ◽  
Andrew Hall ◽  
Katrina Walker ◽  
Amy L Sherborne ◽  
Kevin Boyd ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Immune Cell ◽  
Cd8 Cells ◽  
Hla Dr ◽  
Trial Treatment ◽  
Equity Ownership ◽  
First Time ◽  
Immune Profiling

Abstract Background and aims Existing evidence regarding the effect of low-dose cyclophosphamide on immune cells in myeloma patients, in particular in combination with the IMiD® compound pomalidomide is limited. We present here for the first time changes in immune cell sub-group composition associated with the addition of cyclophosphamide to pomalidomide in the randomised MUKseven clinical trial. Material and Methods MUKseven is a randomised phase II study for relapsed or refractory myeloma (RRMM) patients comparing cyclophosphamide (500 mg po d1, 15, 21), pomalidomide and dexamethasone (CPd) versus standard pomalidomide and dex (Pd). Patients with ≥2 prior lines of therapy were randomised 1:1 to CPd or Pd and treated until disease progression. All patients underwent bone marrow sampling and peripheral blood collection, the latter for immune cell immunophenotyping at Cycle 1 Day 1 (C1D1; Baseline), C1D14 (on-treatment), C4D14 (on-treatment) and at disease progression. Peripheral blood (PB) T-cell populations were profiled using multicolor flow cytometry (MFC) designed to assess baseline and pharmacodynamic changes in subpopulations including helper, cytotoxic, naïve, memory, and activated/proliferating phenotypes (CD3, CD4, CD8, CD45RA, CD62L, HLA-DR, Ki67. T-cell sub-populations were defined and their respective % of total lymphocyte population used for downstream analyses. Results In total 102 evaluable RRMM patients were randomised, 51 each to CPd and Pd treatment arms, with comparable clinical baseline characteristics. Patients had received a median of 3 prior lines of treatment. Evaluable PB immune profiling data was available for 93 (91%) patients at Baseline, 83 (81%) at C1D14, 55 (54%) at C4D14 and 26 (25%) at progression. We observed trends for changes in baseline T-cell population composition with increasing numbers of prior lines of therapy. Specifically, mean % CD4+ T-cells decreased from 35% for patients with 2 prior lines (n=18) to 30% with 3 (n=33), 23% with 4 and 20% with ≥5 prior lines of treatment (n=27), whilst the % of CD8+ cells were similar, indicating potential differential cumulative effects of anti-myeloma therapy on T-cell populations. We compared changes in T-cell profiles longitudinally over trial treatment from baseline to C1D14 and C4D14 with summary statistics. Overall, there was a marked increase in activated (HLA-DR+) T-cells with therapy, with a 2-fold increase in mean proportion of activated CD4+ and CD8+ from 3.9% and 10.2% at baseline to 7.8% and 19.9% at C1D14 and 7.2% and 28.2% at C4D14, respectively (Figure 1). Trial treatment was associated with a shift in sub-populations within CD8+ T-cells in particular, with a relative % decrease in naïve (CD45RA+) sub-populations and increase in memory (CD45RA-) populations. To identify differences associated with cyclophosphamide treatment a regression analysis was conducted on the C1D14 time point accounting for the treatment a patient received and incorporating their baseline (C1D1) measurement. The mean% estimates for total T-cells (CD3+) at C1D14 were significantly higher for the CPd arm in comparison to Pd: 72.1% [95% CI: 66.5 - 73.6] vs. 64.2% [58.2 - 66.1] (P=0.004). Estimates for the Pd arm appeared similar to baseline [mean C1D1: 61.7%]. Mean% estimates for CD8+ and CD4+ cells were also significantly higher with CPd treatment at C1D14 compared to Pd: 37.2% [32.6 - 38.0] vs. 33.1% [28.5 - 33.7] (P=0.03) and 26.2% [21.6 - 27.0] vs. 21.8% [21.6 - 27.0] (P=0.016), respectively. Importantly, mean% estimates for activated (HLA-DR+) CD4+ cells were significantly higher for the CPd arm 10.1% [6.9 - 9.4] vs 8.1% [5.1 - 7.2] in the Pd arm (P =0.02). There was a trend for additional increase of activated CD8+ cells by addition of cyclophosphamide to Pd therapy (P=0.06). Discussion We demonstrate for the first time in a randomised trial using systematic longitudinal immune profiling that addition of cyclophosphamide to pomalidomide and dexamethasone is significantly associated with altered T-cell profiles and an increased proportion of activated T-cells. MUKseven clinical endpoint data are reported separately, with improved response rates observed for CPd vs. Pd. Correlation of immune profiles with clinical outcomes and tumour genetics will be presented at the conference when PFS outcome data will be mature. Disclosures Boyd: Novartis: Consultancy, Honoraria; Janssen: Honoraria, Other: Travel and Accommodation expenses; Celgene: Consultancy, Honoraria, Other: Advisory role. Garg:Janssen: Honoraria; Novartis: Other: travel support, Research Funding; Takeda: Other: Travel Grant; Amgen: Honoraria, Other: Travel Support. Pawlyn:Janssen: Honoraria, Other: Travel support; Celgene Corporation: Consultancy, Honoraria, Other: Travel support; Amgen: Consultancy, Honoraria, Other: Travel Support; Takeda Oncology: Consultancy, Other: Travel support. Pierceall:Celgene: Employment, Equity Ownership. Cook:Celgene Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Seattle Genetics: Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Thakurta:Celgene Corporation: Employment, Equity Ownership. Kaiser:Chugai: Consultancy; Takeda: Consultancy, Other: travel support; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Other: travel support; Amgen: Consultancy, Honoraria.

Number of PD-1+/CD8+ Cells in Peripheral Blood of Patients with Lymphoma Reflects Tumor Burden, Lymphoma Subtype, Disease Phase and Is Significantly Higher Compared to Healthy Volunteers.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2670-2670
Author(s):  
Vit Prochazka ◽  
Martin Novák ◽  
Zuzana Pikalova ◽  
Tomas Papajik ◽  
Karel Indrak ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Healthy Volunteers ◽  
Peripheral Blood ◽  
Healthy Subjects ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Disease Stages

Abstract Abstract 2670 Background: Programmed death-1 (PD-1) and programmed death-1 ligand (PD-L) signaling pathways are involved in the functional impairment and “exhaustion” of cytotoxic CD8+ T cells in conditions such as chronic viral infection and in tumor immune evasion. The interaction of PD-1 with its ligand PD-L suppresses antitumor T cell function and indirectly stimulates Treg population. We investigated a hypothesis of whether examining PD-1 expression in peripheral T cells of patients with different lymphoma subtypes reflects tumor subtype or stage and compared results with healthy volunteers. Methods: Patients were assessed prior to their treatment or at the time of disease relapse or progression. We analyzed 5 patients with HL and 30 patients with NHL (T-cell n=6, diffuse large B-cell n=12, follicular lymphoma n=9, marginal zone lymphoma n=3). Twelve of the patients had relapsed or refractory diseases (B-NHL n=6, T-NHL n=2, HL n=4). Eleven patients (32%) had advanced (III/IV) disease stages. Data were compared with samples obtained from 12 healthy blood donors. Peripheral blood samples were stained with anti-CD3 FITC (Exbio), PD-1 (CD279) PE (BioLegend), anti-CD8 PerCP (Exbio), CD4 APC (Exbio), anti-CD25 FITC (BD), and anti-CD127 PE (BioLegend) using a lyse/no-wash protocol. Stained cells were acquired using the FACSCalibur cytometer (BD). Analysis of immunocompetent subpopulations was performed using the CellQuest Pro (BD) software. PD-1 (CD279) population was gated from CD3-positive T cells; minimal acquisition was designated as 10,000 CD3+ events. The percentage of PD-1+ cells within the live CD3+CD4+ and CD3+CD8+ populations was compared to isotype controls to establish baseline values. Absolute numbers were expressed as number of cells*10exp6 per liter. Population of Tregs was defined as CD4+/CD25int-hi / CD127low cells. Tregs were gated from CD4+ lymphocytes with minimal acquisition of 5,000 CD4+ cells. Results: Proportion of PD-1+/CD8+ of CD3+/CD8+ cells was significantly higher in patients with lymphoma than in healthy subjects: healthy volunteers (HV) 8.8%, B-NHL 16.0% (p=0.02), HL 21.8% (p<0.01), and T-NHL 30.8% (p<0.01). In absolute numbers of PD-1+/CD8+ cells, no significant difference was found when comparing healthy subjects and B-NHL: HV 0.23, B-NHL 0.56 (p=0.21), T-NHL 0.93 (p<0.01), and HL 1.51 (p<0.01). When analyzing the proportion of PD-1+/CD8+ cells according to disease phases, the highest numbers were found in patients with refractory/relapsed lymphoma as compared to patients with untreated disease and healthy subjects: HV 8.8%, untreated 14.6% (p=0.04), and relapsed 28.6% (p<0.01). Untreated patients had a significantly lower proportion of PD-1+/CD8+ cells than relapsed patients (p<0.01). Similar results were obtained with absolute numbers: HV 0.22, untreated 0.55 (p=0.03), and relapsed 1.24 (p=0.03). Untreated vs. relapsed patients p=0.05. Patients with limited disease stages had almost the same proportion of PD-1+/CD8+ lymphocytes compared to HV: HV 8.8%, limited stage 11% (p=0.21), and advanced stage 24.3% (p<0.01). In absolute numbers, HV had much less PD-1+/CD8+ cells in PB: HV 0.22, limited stage 0.49 (p<0.01), and advanced stage 0.97 (p<0.01). When analyzing the population of PD-1+/CD4+ cells, differences were only found in absolute numbers between HV (0.35) and HL (1.34; p<0.01), and between B-NHL (0.54) and HL (p=0.01). Regarding the population of Tregs, statistical differences were found between HV and B-NHL, HL or T-NHL in either relative or absolute numbers. On the other hand, there was a close correlation between absolute numbers of Tregs and PD-1+/CD4+ cells (p<0.01, correlation 0.73), and between Tregs and PD-1+/CD8+ cells (p<0.01, correlation 0.53). Conclusion: PD-1 expression in peripheral blood CD4+ and CD8+ cells is markedly different between lymphoma subtypes and compared with healthy subjects. The highest numbers of PD-1+/CD8+ are in patients with advanced lymphoma and at the time of disease relapse. This fact support the hypothesis that tumor clones actively switch effector CD8+ cells through the PD1L/PD-1 pathway into an immunotolerant state. PD-1 may be a potential marker of systemic immune dysregulation in lymphoma patients and further exploration of T cell subpopulations may define its role as a potential biomarker. Supported by grants: MSM 6198959205, LF-2012-007 and MZ ÈR IGA NT 11103. Disclosures: Prochazka: Roche: Travel grants Other.

Immune Dysfunction in Patients with MDS Is Partially Corrected in EPO-Treated Patients: Differences According to WHO Classification

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3165-3165
Author(s):  
Howard S Oster ◽  
Naamit Deshet-Unger ◽  
Drorit Neumann ◽  
Moshe Mittelman ◽  
Nir Maaravi ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Cd8 T Cells ◽  
Healthy Subjects ◽  
Advanced Disease ◽  
Fold Increase ◽  
Refractory Anemia ◽  
Cd8 Cells ◽  
Cell Numbers

Abstract Background: The immune system has been shown to be involved in the pathogenesis of myelodysplastic syndromes (MDS), and is also affected by the disease. Recombinant erythropoietin (rHuEPO), or in general, erythroid stimulating agents (ESAs) have become a standard treatment for anemic patients with MDS. They were found to improve anemia, quality of life, and possibly survival. We have previously demonstrated that EPO has effects on cellular and humoral immunity and specifically, on immune function in patients with multiple myeloma (MM). Here we report our findings demonstrating the effect of ESAs on T cell (CD4+, CD8+ and CD4+CD25+) number and function in patients with MDS. Patients and Methods: We examined three groups: healthy subjects ('Control', 20 participants), MDS patients without ESA treatment ('MDS', 13), and MDS patients treated with an ESA ('MDS+EPO', 17). All diagnosed patients gave informed consent as approved by our IRB. Cell numbers were evaluated with flow cytometry. In a subset of patients, cell activation was assessed in response to phytohemagglutinin (PHA) by examining CD69 expression in both CD4+ and CD8+ cells. The co-stimulatory marker, CD28, and the inhibitory marker CTLA-4 (CD152) were evaluated as well. We also examined World Health Organization (WHO) subgroups, refractory anemia (RA) and RA with ringed sideroblasts (RARS) versus more advanced disease. Results: CD4+ and CD8+ T cell levels are reduced and increased respectively in MDS patients compared to control, and these changes are reversed in MDS+EPO (Table 1, CD4+, p<0.01; CD8+, p=0.05). The CD4+:CD8+ ratio (Table 1) is reduced and nearly equalized in MDS (1.16), but approaches that of the control (2.24) in MDS+EPO (1.94). CD4+CD25+ T cell numbers (including regulatory T cells), were lower in MDS patients and improve in the MDS+EPO group (Table 1). In vitro activation of T cells (CD4+CD69+ and CD8+CD69+) achieves an approximately 15-fold increase in healthy subjects. MDS patients without EPO sustained only a 7.17 fold increase in CD4+ activation versus 13.64 fold for the MDS+EPO group (p<0.01); for CD8+ T cells, 10.20 fold (MDS) versus 18.56 fold (MDS+EPO, p<0.01). The expression of the co-stimulatory marker CD28 was decreased in both CD4+ and CD8+ T cells in MDS, and approached normal in MDS+EPO in CD4+ T cells (Table 1). There was no significant change in inhibitory CTLA-4 (CD152) expression among the groups (not shown). Subgroup analysis demonstrated that ESA has a similar effect on CD4+ and CD8+ cells and their ratio in both RA/RARS and more advanced disease, similar to those of the whole cohort (Table 2, green). On the other hand, some parameters were affected by ESA only in one subgroup (Table 2, blue): The ESA effect on CD4+CD25+ cells was evident only in patients with advanced disease (Table 2, blue). ESA affected CD4+ and CD8+ cell stimulation (CD69) in RA/RARS, similar to that seen in the whole cohort (Table 2, blue). Of note, in more advanced disease, CD4+ and CD8+ cells achieved stimulation in the MDS group not treated with ESA, with no difference between MDS and MDS+EPO. This finding needs to be further addressed in larger cohorts and with additional markers of activation. Conclusions: MDS patients display T-cell abnormalities that are improved upon EPO treatment. MDS is a heterogeneous disease where the immune system both affects and is affected by the disease. As such, treatment with ESAs might ameliorate not only the anemia, but also the immune deficiencies and perhaps the disease itself. Future studies will clarify the immunomodulatory role of ESA in the various stages of MDS. Disclosures No relevant conflicts of interest to declare.

scholarly journals Omicron-specific cytotoxic T-cell responses are boosted following a third dose of mRNA COVID-19 vaccine in anti-CD20-treated multiple sclerosis patients

2021 ◽  
Author(s):  
Natacha Madelon ◽  
Nelli Heikkila ◽  
Irene Sabater Royo ◽  
Paola Fontannaz ◽  
Gautier Breville ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vaccine Dose ◽  
T Cell Responses ◽  
Antibody Responses ◽  
Cytotoxic T Cell ◽  
Cell Responses ◽  
The Third ◽  
Before And After ◽  
Anti Cd20

Importance: The SARS-CoV-2 variant Omicron escapes neutralizing antibody responses elicited after COVID-19 vaccination, while T-cell responses might be better conserved. It is crucial to assess how a third dose of vaccination modifies these responses, particularly for immunocompromised patients with readily impaired antibody responses. Objective: To determine T-cell responses to the Spike (S)-protein of Omicron in anti-CD20 treated patients before and after their third mRNA COVID-19 vaccination Design: Prospective observational monocentric study Setting: Conducted since March 2021 at the University Hospital Geneva Participants: Twenty adults with multiple sclerosis on anti-CD20 treatment (ocrelizumab) who received their third dose of mRNA COVID-19 vaccine 6 to 7 months after their second vaccination. Intervention: Blood sampling before and one month after the third vaccine dose Main outcomes and measures: Quantification of CD4 and CD8 (cytotoxic) T cells specific for SARS-CoV-2 S-protein of vaccine strain, Delta and Omicron variants , using activation marker induced assay (AIM) and comparing frequencies before and after the third vaccine dose. Results: S-specific CD4 and CD8 T-cell memory against all variants was maintained in around half of the patients six months after their second vaccination, albeit at lower frequencies against Delta and Omicron variants. A third dose enhanced the number of responders to all variants and significantly increased CD8 T-cell responses. The frequencies of T cells specific to Omicron and Delta remained lower than those specific to the vaccine strain after the boost. Conclusion and relevance: Vaccinated MS patients on anti-CD20 treatment show robust T-cell responses that recognize S from the circulating Delta and Omicron variants. Response rates increased after the third dose, demonstrating that a booster dose might improve cytotoxic T-cell mediated protection against severe disease in patients with low humoral response. The clinical relevance of the reduced frequencies of T cells specific to Omicron will need to be monitored in the future.

Dendritic Cell Vaccination in Acute Leukemia Patients Induces Reduction of Myeloid-Derived Suppressor Cells : Immunological Analysis of a Pilot Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1113-1113 ◽  
Author(s):  
Masahiro Ogasawara ◽  
Shuichi Ota
Keyword(s):  
T Cells ◽  
Acute Leukemia ◽  
Suppressor Cells ◽  
Absolute Number ◽  
The Other ◽  
Myeloid Derived Suppressor Cells ◽  
Arginase 1 ◽  
Hla Dr ◽  
Healthy Donors ◽  
Before And After

Abstract Background and Purpose: Myeloid-derived suppressor cells (MDSC) are a heterogeneous cell population that have an immunesuppresive function and play an important role in tumor immunology and self tolerance. Elevated levels of MDSCs in peripheral blood (PB) are reported in various cancers and hematological malignancies such as MDS, NHL and MM. We reported that vaccination with Wilms’ tumor 1 (WT1) peptide-pulsed dendritic cells (DC) in NHL patients induced not only WT1 specific immune responses but also innate immunity which correlated with clinical efficacy (ASH 2013). In the present study, we focused on MDSCs and investigated the effects of DC vaccination on the alteration of MDSCs which have negative influence on disease progression. Patients and Methods: 8 patients with acute leukemia (6 AML and 2ALL patients; aged 16-77) who were treated with WT1 peptide-loaded DC vaccination were enrolled in the present study. MDSCs were analyzed by FACS. Linage negative, CD11b+CD33+HLA-DR- cells were defined as MDSC. Monocytic and granulocytic MDSC were defined as CD14+HLA-DRlow/- and CD15+CD11b+CD33+HLA-DR-, respectively. For proliferation assay, CD14+DR- cells and CD3+ T cells were isolated by magnetic beads method. CFSE-labeled CD3+ T cells were stimulated with anti-CD3 and anti-CD28 moAb together with IL-2 in the presence or absence of CD14+DR-cells for 4 days and cell division was analyzed by FACS. Cytoplasmic staining of indoleamine 2,3-deoxygenase (IDO) and arginase 1 were performed by permeabilization using saponin followed by moAb staining. Arginase 1 protein levels in plasma was assessed using a commercially available ELISA kit. Results: 3 patients were in complete remission (responder) and 5 others were in disease progression (non-responder) following one course of vaccination. WT1 specific T cell responses evaluated by a HLA-tetramer assay and a delayed type hypersensitivity (DTH) test were observed in all the responders and 2 non-responders. Mean percentage of MDSCs, monocytic and granulocytic MDSCs in PB was higher in acute leukemia patients than in healthy donors (1.60±0.72%, 16.56±6.07%, 1.34±0.69%, respectively in patients; 0.60±0.31%, 13.1±4.1%, 0.37±0.1%, respectively in healthy donors). Absolute number of circulating monocytic and granulocytic MDSCs before and after vaccination in responders was 359.4±117.8/μl and 35.2±14.8/μl, 282.8±119.2 /μl and 14.4±12.0/μl, respectively. On the other hand, those in non-responders were 126.3±60.2/μl and 36.3±21.7/μl, 181.3±124.0/μl and 65.1±12.0/μl, respectively. While DC vaccination resulted in reduction of both monocytic and granulocytic MDSCs by 21.3% and 59.1%, respectively in responders, it induced augmentation of these MDSCs by 43.5% and 79.3%, respectively in non-responders. A portion of MDSCs expressed IDO and arginase 1 in cytoplasm. While the percentage of IDO positive cells in monocytic MDSCs increased by 2.2 and 2.3 times in responders and non-responders, respectively following vaccination, the positivity of arginase 1 decreased by 59% in responders. On the other hand, the positivity of IDO and arginase 1 in granulocytic MDSCs decreased at the same level in both responders and non-responders following vaccination. CD14+DR-cells inhibited the proliferation of CD3+ T cells in a dose dependent manner, indicating that these cells share characteristics of MDSCs. The inhibition of the proliferation of CD3+T cells was partially restored by the addition of 1-methyl-DL-tryptophan (IDO inhibitor) and Nω-hydroxy-nor-arginine (arginase 1 inhibitor), suggesting that the inhibition was mediated at least in part by IDO and arginase 1. Amount of arginase 1 in the plasma before and after vaccination decreased by 25% in responders, not in non-responders. Conclusions: These results demonstrated that DC vaccination resulted in the reduction of the absolute number of MDSCs which seems to be correlated with clinical efficacy. DC vaccination may have inhibitory effects on several functions of MDSCs that can suppress immune surveillance against leukemia, which is favorable for regression of leukemia cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Generation of antigen receptor-specific suppressor T cell clones in man.

1986 ◽  
Vol 164 (3) ◽  
pp. 950-955 ◽  
Author(s):  
N Mohagheghpour ◽  
N K Damle ◽  
S Takada ◽  
E G Engleman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Receptor ◽  
Suppressor Cells ◽  
Suppressive Effect ◽  
T Cell Clones ◽  
Suppressor T Cell ◽  
Hla Dr ◽  
Cell Clones

We have shown previously that CD8+ T cells proliferate upon exposure to autologous, antigen primed CD4+ T cells, and suppress the response of fresh T cells to the priming antigen but not irrelevant antigens. The stimulus and target of suppression in this system appears to be the antigen receptor on the surface of CD4+ cells, rather than the nominal antigen. In the current study, alloantigen primed CD4+ inducer cells and IL-2-containing medium were used to generate clones of suppressor cells from several individuals. The clones inhibited the response of fresh autologous T cells only to the original allogeneic stimulator cell and to stimulator cells that shared HLA-DR antigens with the priming cell. The clones were also genetically restricted, since they inhibited the response of HLA-A,B-compatible but not HLA-A,B-incompatible individuals. The availability of a method for reproducibly generating antigen receptor-specific suppressor T cell clones in vitro should make it possible to clarify the mechanism, whereby such cells are activated and exert their suppressive effect.

scholarly journals Mercury-induced autoreactive anti-class II T cell line protects from experimental autoimmune encephalomyelitis by the bias of CD8+ antiergotypic cells in Lewis rats.

1993 ◽  
Vol 177 (4) ◽  
pp. 881-889 ◽  
Author(s):  
M Castedo ◽  
L Pelletier ◽  
J Rossert ◽  
R Pasquier ◽  
H Villarroya ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Cell Line ◽  
Suppressor Cells ◽  
Class Ii ◽  
Autoimmune Encephalomyelitis ◽  
Autoreactive T Cells ◽  
Cd8 Cells ◽  
Experimental Autoimmune

Brown-Norway (BN) rats injected with HgCl2 develop a systemic autoimmune disease associated with a polyclonal B cell activation, due to autoreactive T cells specific for self-class II molecules, while Lewis (LEW) rats injected with HgCl2 do not exhibit autoimmunity and develop a non-antigen-specific, CD8-mediated immunosuppression assessed by a depression of T cell functions, and a protection against experimental autoimmune encephalomyelitis (EAE). Resistance to HgCl2-induced autoimmunity is not due to these suppressor cells since treatment with an anti-CD8 monoclonal antibody (mAb) did not allow autoimmunity to appear. The absence of autoimmunity in this strain could result from the absence of autoreactive T cells, or from quantitative or qualitative differences of these cells between susceptible and resistant strains. In the present study, we show that CD4+ anti-class II T cells are present in HgCl2-injected LEW rats and are as frequent as in BN rats when assessed by limiting dilution analysis. LEW CD4+ autoreactive T cell lines were derived. They proliferated in the presence of normal class II-bearing cells, secreted interleukin 2, and did not induce B cells to produce immunoglobulins. Transfer of one of these lines, LEW Hg A, into normal LEW rats led to the appearance of CD8+ cells responsible for a non-antigen-specific immunosuppression that induced complete protection from EAE. Immunosuppression was abrogated after treatment with an anti-CD8 mAb. In vitro, CD8+ cells from rats injected with the LEW Hg A T cell line proliferated in the presence of activated T cells whatever their origin. We conclude that HgCl2 induces CD4+ autoreactive T cells that proliferate in the presence of class II+ cells in susceptible BN as well as in resistant LEW rats. But while these cells collaborate with B cells to produce autoantibodies in BN rats, they initiate in LEW rats a suppressor circuit involving antiergotypic CD8+ suppressor cells.

scholarly journals In CLL, Myeloid-Derived Suppressor Cells and Their Monocytic and Granulocytic Varieties Differ in T-Cell Subset Association and Polarization Induction

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4350-4350
Author(s):  
Gerardo Ferrer ◽  
Brendan Franca ◽  
Pui Yan Chiu ◽  
Stefano Vergani ◽  
Andrea Nicola Mazzarello ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Research Funding ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Cd8 Cells

Abstract In chronic lymphocytic leukemia (CLL) monoclonal B cells expand and progressively accumulate in the bone marrow, eventually migrating to secondary lymphoid organs for even greater proliferation. At both sites, CLL cells engage in complex, incompletely defined cellular and molecular interactions involving multiple cell types such as T cells, myeloid cells, mesenchymal stromal cells, and matrix, collectively referred to as the "tumor microenvironment". This microenvironment is critical for the survival and proliferation of CLL cells, and data indicate that T cells and myeloid cells have an important role in these processes. In this study, we focus on two cells types: CD4+ T lymphocytes and myeloid-derived suppressor cells (MDSCs). In CLL patients, these populations are altered and impact on clinical outcome. CD4+ T cells comprise several subtypes, and CLL patients often have expanded Th2 and Tregs populations, consistent with the immunosuppressive status of these patients. Moreover, patients with higher numbers of another CD4+ subset, Th17 cells that produce IL-17 and other pro-inflammatory cytokines, can have longer survival times. Although studied minimally in CLL, MDSCs are known suppressors of T cell proliferation in vitro, and expand along with malignant cells in several cancers. However, no information is available about their effects on CD4+ T cell differentiation or on B-cell biology in CLL. In a cohort of 56 untreated CLL patients, we first explored correlation of the numbers of MDSCs and autologous T cells, using flow cytometry. CD3+ cell numbers significantly paralleled total MDSCs and monocyte-like MDSCs (mMDSCs) (P = 0.002, Spearman r = 0.44; P = 0.004, Spearman r = 0.41, respectively). Interestingly, MDSCs correlated with CD4+ and CD8+ T-cells (P < 0.001, Spearman r = 0.646; P < 0.001, Spearman r = 0.61, respectively). However, the correlation of MDSC subpopulations with CD4+ and CD8+ cells differed: mMDSCs associated significantly with CD4+ cells (P < 0.001, Spearman r = 0.73) and granulocyte-like MDSCs (gMDSCs) with CD8+ cells (P= 0.008; Spearman r = 0.45). Furthermore, although gMDSCs did not correlate with the numbers of CD4+ T-cells, we observed that they positively paralleled Tregs defined as CD3+/CD4+/CD25+/CD127-/FoxP3+ cells (P = 0.020, Spearman r = 0.44). Other subpopulations are currently under study. To address the effect of MDSCs on CD4+ cell differentiation, we FACS sorted CD3+/CD45RO- naïve CD4+ lymphocytes and stimulated them in vitro with anti-CD3/CD28 beads and IL2 in the presence or absence of mMDSCs (HLA-DRlo/CD11b+/CD33+/CD14+), gMDSCs (HLA-DRlo/CD11b+/CD33+/CD15+) or monocytes (HLA-DRhi/CD11b+/CD14+); these studies involved samples from 3 CLLs and 3 healthy controls (HCs). On day 7, cells were harvested and cytokine production was quantified by intracellular flow cytometry as the percentages of the following populations: Th1 (INFγ), Th2 (IL-4), Tregs (FoxP3), Th17 (IL-17A and IL-17F), Th9 (IL-9) and Th22 (IL-22). Culturing CLL or HC T cells in the absence of MDSCs revealed a lower percentage of cytokine-producing cells (24% vs. 55%; P = 0.017) in CLL, which was mainly due to a reduction in IL-4+ cells (P = 0.066). However, when analyzing the effects of MDSC subsets on the polarization of CLL or HC T cell, gMDSCs promoted significantly more FoxP3+ and less IL-22+ cells in CLL than in HC (P = 0.025 and P = 0.048, respectively). When analyzing only CLL T cells, supplementation with mMDSCs induced a reduction in IL-22+ cells (P = 0.027) and an insignificant increase of IL-4+ and IL-17+ cells. Conversely monocytes supported an expansion of INFγ+ T-cells (P=0.066), and gMDSCS promoted an increase of IL-9+ cells (P = 0.046) and a reduction of FoxP3+ cells (P = 0.019). In summary, in CLL the absolute numbers of total MDSCs and T cells are tightly linked. There is a significant correlation between CD4+ T cells and mMDSCs, and between CD8+ T cells and gMDSCs. Additionally, in CLL naïve CD4+ differentiation appears reduced compared to HC, in concordance with lower T-cell responses previously reported. Moreover, the preliminary aspects of the study suggest that CLL mMDSCs promote an expansion of Th2, Th17 cells and a reduction of Th22 cells, and monocytes enhance Th1s. Unexpectedly, since we observed a significant positive correlation in the PBMCs, gMDSCs may reduce Tregs and augment Th9. These findings depict differential consequences of CLL T cell - MDSC / mMDSC / gMDSC interactions. Disclosures Stamatopoulos: Abbvie: Honoraria, Other: Travel expenses; Gilead: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding.

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