Trapping and apoptosis of novel subsets of memory T lymphocytes expressing CCR6 in the spleen of HIV-infected patients

Blood ◽  
2006 ◽  
Vol 109 (9) ◽  
pp. 3649-3657 ◽  
Author(s):  
Cédric Lécureuil ◽  
Béhazine Combadière ◽  
Elodie Mazoyer ◽  
Olivia Bonduelle ◽  
Assia Samri ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Effector Memory ◽  
Memory T Cell ◽  
Effector Memory T Cells ◽  
Tnf Α ◽  
T Cell Homing ◽  
Cell Subpopulations ◽  
Specific Stimulation ◽  
T Cell Subpopulations

AbstractCCR6, a homeostatic chemokine receptor, is shown here to characterize subsets of both central and effector memory T cells that secrete high levels of IL-2 and TNF-α in response to polyclonal and antigen-specific stimulation. CCR6+ T lymphocytes disappeared dramatically from the peripheral blood of HIV-infected patients as HIV disease progressed. The capacity of CD4+CCR6+ to secrete multiple cytokines remained intact among HIV-infected long-term nonprogressors but was partially lost from subjects with standard disease progression. CCR6+ T lymphocytes, regardless of their CCR7 expression, accumulated in the spleen of HIV-infected patients, where they died by apoptosis. Assessment of CCR6 expression allowed us to describe novel memory T-cell subpopulations capable of high cytokine production and provided evidence of a pathologic CCR6-dependent pathway of memory T-cell homing that may participate in the loss of memory response against infections.

Loss of Normal T-Cell Subset Distribution in Myelofibrosis Is Recovered By the Immunomodulatory Effects of JAK1/2 Inhibition

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3138-3138
Author(s):  
Sanja Prijic ◽  
Taghi Manshouri ◽  
Ivo Veletic ◽  
Kate J Newberry ◽  
Ying Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytokine Production ◽  
Memory T Cells ◽  
Cell Subset ◽  
Effector Memory ◽  
Spleen Size ◽  
Effector Memory T Cells ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Abstract Introduction: Myeloproliferative neoplasms (MPN) are clonal disorders of the hematopoietic system characterized by an excessive proliferation of myeloid cells and progressive bone marrow fibrosis. MPNs are result of an abnormal constitutive activation of the JAK/STAT signaling pathway. Ruxolitinib is the first JAK1/2 inhibitor approved for the treatment of myelofibrosis (MF), the most aggressive of MPNs. However, the beneficial effects of ruxolitinib cannot be attributed to its anticlonal activity but rather to its reduction in inflammatory cytokine production, spleen size and symptom burden. Helper (CD4+) and cytotoxic (CD8+) T-cells are key mediator elements in the adaptive immune system. Disrupted homeostasis of functionally diverse T-cell subpopulations (naïve, memory and effector) can result in abnormal cytokine production. The aim of this study was to determine the baseline T-cell subset composition in patients with MF and to monitor the immunomodulatory effects of JAK1/2 inhibition. Methods: CD4+ and CD8+T-cell subpopulations were measured in PB samples from healthy controls (n=16) and PB and BM samples from patients (n=47) with MF treated on a phase I/II clinical trial of ruxolitinib, using multiparametric flow cytometry. Subsets were immunophenotypically defined based on the cell-surface expression of CD45RO and CD62L as follows: naïve T-cells, CD45RO-CD62L+; central memory (CM), CD45RO+CD62L+; effector memory (EM), CD45RO+CD62L-; and terminally differentiated effector memory T-cells (TEM) CD45RO-CD62L-. Results: Our results showed no significant difference in the distribution of helper vs. cytotoxic T-cells between untreated MF patients and healthy subjects. Nevertheless, profound alterations in both the CD4+ and CD8+ compartments were found in MF patients. Patients with MF had significantly fewer antigen inexperienced naïve (38.7±3.1% vs. 12.9±2.0%, p<0.0001; 26.5±2.6% vs. 7.0±1.2%, p<0.0001) and central memory (23.9±1.7% vs. 6.9±0.9%, p<0.0001; 10.7±1.1% vs. 2.7±0.4%, p<0.0001) T-cells than control subjects. At the same time, terminally differentiated effector memory T-cells were significantly increased in MF patients (13.0±1.0% vs. 44.0±2.5%, p<0.0001, 26.6±2.4% vs. 58.3±2.2%, p<0.0001). To determine the effects of JAK1/2 inhibition on the T-cell subset distribution, we compared baseline (n=47) T-cell subsets with on-treatment (n=49) patient samples. Median follow-up time was 2.8 years (range: 0.2-8.0 years). We found that ruxolitinib administration increased the naïve and CM T-cells in both the CD4+ (12.9±2.0% vs. 20.1±1.4%, p=0.011; 6.9±0.9% vs. 18.3±1.2%, p<0.0001) and CD8+ populations (7.0±1.2% vs. 11.4±1.1%, p=0.02; 2.7±0.4% vs. 5.4±0.5%, p=0.0001), whereas it decreased TEM (44.0±2.5% vs. 25.5±1.7%, p<0.0001; 58.3±2.2% vs. 48.8±2.4%, p=0.0072). Remarkably, only patients who achieved a ≥50% spleen size reduction (SR) had a significant increase in naïve CD4+ (11.0±2.5% vs. 24.2±1.8%, p=0.0002, compared with 17.0±5.2% vs. 16.0±2.4%, p=0.98 for SR <50%) and CD8+ T-cells (5.4±1.3% vs. 12.3±1.5%, p=0.0036, compared with 10.4±3.2% vs. 9.3±2.3%, p=0.96 for SR <50%) during ruxolitinib treatment. Conclusions: In patientswith MF, T-cell subsets are skewed towards the effector phenotype. It has been shown that terminally differentiated effector memory T-cells are generated as a result of cytokine-driven rather than antigen-driven proliferation and differentiation stimuli. These highly efficient effector cells produce vast amounts of pro-inflammatory cytokines that account for and/or contribute to the chronic inflammatory milieu commonly found in MF. The JAK1/2 inhibitor reverses the equilibrium towards naïve T-cell phenotype to some extent, possibly contributing to the diminished cytokine production seen after JAK1/2 inhibition. This effect is more pronounced in patients with a better response, as measured by the degree of spleen size reduction. In conclusion, even though MF is a disease of the myeloid lineage, we show evidence of severe immune derangements in T-cell subpopulations. Ruxolitinib might exert its benefit for MF patients due to its modulating effect on T-cells known to produce high cytokine levels. Disclosures No relevant conflicts of interest to declare.

scholarly journals Selective expression of H-2 (i-region) loci controlling determinants on helper and suppressor T lymphocytes.

1976 ◽  
Vol 144 (3) ◽  
pp. 685-698 ◽  
Author(s):  
K Okumura ◽  
L A Herzenberg ◽  
D B Murphy ◽  
H O McDevitt ◽  
L A Herzenberg
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Lymphoid Cells ◽  
Control Surface ◽  
Cell Subpopulation ◽  
Selective Expression ◽  
Suppressor T Lymphocytes ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Data presented here show that locidentify in the I-region of the H-2 gene complex are selectively expressed in different functional T-cell subpopulations. These loci are closely linked (or possibly identical) to loci that control immune responses. They control surface determinants which identify helper and suppressor T lymphocytes. Determinants described here on allotype suppressor T cells (Ts) are found on normal (nonsuppressed) lymphoid cells, but are not found on helper T cells (Th). These determinants are controlled by a locus mapping in the I region of the H-2 complex. In an accompanying publication we show that this locus (Ia-4) marks a new I subregion (I-J) and is expressed only on T cells. Thus Ia-4 determinants idenfity a T-cell subpopulation which includes Ts but not Th. Th also carry identifying surface determinants controlled by loci that map to the H-2 complex, probably within the I region. These determinants are not found on Ts. Data presented also establish that loci in the I region control determinants on Th, but do not conclusively demonstrate that these are the determinants that distinguish Th from Ts. The selective expression of H-2-controlled determinants on Ts and Th suggests that these determinants are directly involved in immunoregulation.

Correlative Analysis of T Cell Subpopulations and CD20 Expression In a Phase II Study of Lenalidomide In Combination with Rituximab In Patients with Relapsed or Refractory CLL/SLL

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4630-4630
Author(s):  
Marays Veliz ◽  
John Powers ◽  
Ling Zhang ◽  
Enrique Santana ◽  
Jeffrey E. Lancet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Effector Memory ◽  
Time Points ◽  
Cd20 Expression ◽  
Correlative Studies ◽  
Cell Subpopulations ◽  
Grade 3 ◽  
T Cell Subpopulations

Abstract Abstract 4630 Background: The prognosis of patient with relapsed or refractory CLL/SLL is dismal with an overall response rate (ORR) to salvage therapy for refractory patients of 10–30%, and limited survival benefit with current treatment approaches. Phase II studies of single agent lenalidomide in patients with relapsed or refractory CLL revealed an ORR of 32–58% (7-17% CR). Recent in vitro studies have shown that lenalidomide enhances the rituximab-induced killing of NHL cell lines and B-CLL cells by enhancing ADCC activity and restoring the defective T-cell and NK-cell mediated tumor cell cytotoxicity. Methods: Patients with relapsed or refractory CLL/SLL received oral lenalidomide via dose escalation as follows: 2.5 mg on days 1–7, 5 mg on days 8–14 and 10 mg on days 15–21 followed by 7 days of rest in 28-day cycle; for cycle 2 and beyond 20 mg was given on days 1–21 on a 28-day cycle. Rituximab was dosed at 375 mg/m2 IV weekly for 4 weeks starting on day 15 of cycle 1. Treatment was continued until disease progression or toxicity. Primary objectives were ORR (CR+PR) and safety and tolerability of the combination regimen. CT scans, and bone marrow biopsies were done every 2 months to assess for response (NCI-WG 2008). Peripheral blood and bone marrow aspirates were collected for correlative studies before lenalidomide was initiated, before rituximab was initiated (between days 13–15), after finishing treatment with rituximab and then every two months until disease progression. Flow cytometry was performed using the following antibodies CD3, CD4, CD5, CD8, CD19, CD20, CD23, CD40, CD45RA, CD62L, CD80, CD86, CD95, IL-17A and FoxP3. Panels were created for the analysis of T-cell memory/naïve populations, B-cell populations, regulatory T-cells and Th17 cells. Data was collected to a limit of 10,000 events of the population of interest. Data is presented as total number of cells/ul instead as percentage to avoid misinterpretation due to the dramatic reduction in the number of B cell lymphocytes after initiation of therapy. Subpopulation of T cells memory/naïve were compared with an age matched population of normal controls. Results: 18 patients with CLL/SLL were enrolled on study. Median number of prior chemotherapies was 3 (range 1–5). Median age was 63 years (range 42–80). High risk cytogenetic abnormalities (del11q (11%), del 17p/p53 (11%), complex (22%)) were observed in 44% of the patients. 95% of the patients had received prior fludarabine therapy and 50% were fludarabine refractory. Overall clinical benefit was seen in 92% of patients (42% PR, 50% SD) with a median duration of response of 18 months for patients who achieved a PR and 12 months for patients with SD. Although all responses were PR, the PR rate improved with continued therapy suggesting increased responses with a longer duration of treatment with lenalidomide. Most common adverse effects were neutropenia (50% grade 3–4), tumor flare (28% grade 1–2, 11% grade 3–4), fatigue (11% grade 1–2, 6% grade 3–4), venous thromboembolic disease (11% grade 3–4), acute renal insufficiency (11%), rituximab related infusion reactions (11%), flu-like symptoms (11%), infections (11%), and hypercalcemia (11%). Correlative studies showed that peripheral blood CD4 and CD8 effector memory subpopulations decreased after initiation of lenalidomide therapy with subsequent elevation after rituximab treatment on the CD4 effector memory compartment. The Th17 compartment was minimally decreased after initiation of lenalidomide while the levels of regulatory T cells (Tregs) appeared to decrease with lenalidomide therapy and increase slightly after rituximab. The expression of CD20 from bone marrow samples decreased as expected with rituximab therapy; however shortly after the discontinuation of rituximab CD20 expression was regained by the B cells compartment. Later time points will be presented at the meeting. Conclusions The combination of lenalidomide with rituximab is a promising with clinical activity in heavily pretreated patients with relapsed or refractory CLL. The combination appears tolerable with observed events consistent with the use of these two agents in other studies. The impact of lenalidomide on the T cell subpopulations in patients treated with rituximab remains unclear. A detailed analysis of the BM compartment at latter time points will be investigated. Disclosures: Lancet: Eisai: Consultancy; Celgene: Honoraria. Komrokji:Genentech: Research Funding.

scholarly journals Assessment of CLA+T-cell subpopulations in the blood of patients with chronic dermatoses

2020 ◽  
Vol 96 (4) ◽  
pp. 22-31
Author(s):  
Alexander V. Patrushev ◽  
Alexey V. Samtsov ◽  
Vladimir Yu. Nikitin ◽  
Alexey V. Soukharev ◽  
Oksana P. Gumilevskaya ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
T Cell ◽  
T Lymphocytes ◽  
Lichen Planus ◽  
Cytotoxic T Lymphocytes ◽  
Relative Number ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
The Relationship ◽  
T Helpers

Background. CLA+T-cell are an important component of skin-associated lymphoid tissue, and thus determine the pathogenesis of many immuno-mediated dermatoses. Aims. Determine the relative number of CLA+T-cell subpopulations in the peripheral blood of patients with psoriasis, lichen planus and atopic dermatitis, as well as assess their impact on the severity of dermatoses. Materials and methods. We examined 82 patients with psoriasis aged 19 to 62 years, 54 patients with lichen planus (LP) aged 18 to 54 years, 44 patients with atopic dermatitis (AD) aged 18 to 44 years, as well as 20 practically healthy individuals aged 18 to 52 years who were admitted to the clinic for the removal of benign skin neoplasms. All patients underwent a standard clinical examination with the determination of indicators that characterize the severity of dermatosis: PASI (Psoriasis Area and Severity Index) for patients with psoriasis, IPSLP (index of prevalence and severity of lichen planus) for patients with lichen planus and SCORAD (Scoring of Atopic Dermatitis) for patients with atopic dermatitis. Defining subpopulations CLA+T-lymphocytes were carried out on a flow cytometer Cytomics FC500 by Beckman Coulter using appropriate combinations of direct monoclonal antibodies and isotopic controls. The groups were compared using the nonparametric Mann Whitney test, and the differences were considered significant at p0,05. To analyze the relationship between the severity of dermatosis and the relative content of subpopulations CLA+T-cells used Spearman's rank correlation coefficient. Results. In patients with psoriasis, a significant increase in the percentage of the total number of T-lymphocytes positive for CLA (CLA+CD3+) and T-helpers positive for CLA (CLA+CD4+) (p=0,002 and 8,5104, respectively), in patients with PL and AD only CLA+CD4+ lymphocytes (p=0,028 and 0,003, respectively). In the progressive period of psoriasis, a direct moderate correlation was found between the circulating subpopulation of cytotoxic T lymphocytes positive for CLA (CLA+CD8+) and the PASI index (rs=0,47; p0,001), in the acute period of AD between the CLA+CD3+ subpopulations and CLA+CD4+ cells and the SCORAD index (rs=0,53; p 0,001 and rs=0,57; p0,001, respectively). In PL, the severity of the course of dermatosis was not accompanied by any significant changes in the CLA-positive T-cell subpopulations. Conclusion. The results of the study confirmed the important role of CLA+T cell subpopulations in the development of chronic dermatoses. In all groups (psoriasis, LP and AD), an increase in the relative number of CLA+CD4+ T-helpers was noted compared with the control group. The relationship between the severity of psoriasis and the relative number of CLA+CD8+ cytotoxic T-lymphocytes, and the severity of AD with CLA+CD3+ and CLA+CD4+ T-helpers is also shown.

scholarly journals Distinct CD4−CD8− (Double-Negative) Memory T-Cell Subpopulations Are Associated With Indeterminate and Cardiac Clinical Forms of Chagas Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Livia Silva Araújo Passos ◽  
Carolina Cattoni Koh ◽  
Luísa Mourão Dias Magalhães ◽  
Maria do Carmo Pereira Nunes ◽  
Kenneth John Gollob ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chagas Disease ◽  
Central Memory ◽  
Effector Memory ◽  
Double Negative ◽  
Cytokine Network ◽  
Chagas Cardiomyopathy ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

CD4−CD8− (double-negative, DN) T cells are critical orchestrators of the cytokine network associated with the pathogenic inflammatory response in one of the deadliest cardiomyopathies known, Chagas heart disease, which is caused by Trypanosoma cruzi infection. Here, studying the distribution, activation status, and cytokine expression of memory DN T-cell subpopulations in Chagas disease patients without cardiac involvement (indeterminate form—IND) or with Chagas cardiomyopathy (CARD), we report that while IND patients displayed a higher frequency of central memory, CARD had a high frequency of effector memory DN T cells. In addition, central memory DN T cells from IND displayed a balanced cytokine profile, characterized by the concomitant expression of IFN-γ and IL-10, which was not observed in effector memory DN T cells from CARD. Supporting potential clinical relevance, we found that the frequency of central memory DN T cells was associated with indicators of better ventricular function, while the frequency of effector memory DN T cells was not. Importantly, decreasing CD1d-mediated activation of DN T cells led to an increase in IL-10 expression by effector memory DN T cells from CARD, restoring a balanced profile similar to that observed in the protective central memory DN T cells. Targeting the activation of effector memory DN T cells may emerge as a strategy to control inflammation in Chagas cardiomyopathy and potentially in other inflammatory diseases where these cells play a key role.

scholarly journals Characterization of T-cell Subpopulations in Patients with Chronic Rhinosinusitis with Nasal Polyposis

2017 ◽  
Vol 8 (3) ◽  
pp. ar.2017.8.0214 ◽  
Author(s):  
Pascal Ickrath ◽  
Norbert Kleinsasser ◽  
Xin Ding ◽  
Christian Ginzkey ◽  
Niklas Beyersdorf ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Nasal Polyps ◽  
Nasal Polyposis ◽  
Effector Memory ◽  
Forkhead Box ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Background There is an ongoing discussion concerning the potential origins of chronic rhinosinusitis with nasal polyposis (CRSwNP). Objective The aim of this study was to quantify subpopulations of T cells in peripheral blood and nasal polyps in CRSwNP to examine their influence on the etiology of this disease. Methods Tissue and blood samples were collected from 11 patients who underwent nasal sinus surgery, and these samples were analyzed by multicolor flow cytometry. Results There was a significantly lower frequency of CD4+ T-helper (Th) cells and a significantly higher frequency of CD8+ T cells among lymphocytes isolated from nasal polyps compared with peripheral blood mononuclear cells (PBMC). In both T-cell subpopulations, a shift mainly from naive T cells among peripheral blood lymphocytes toward an effector memory and terminally differentiated subtype predominance in nasal polyps was observed. Among CD4+ T cells, the frequencies of cluster of differentiation (CD) 45RA- Forkhead-Box-Protein P3high (FoxP3high) cytotoxic T-lymphocyte-associated Protein 4high (CTLA-4high) activated regulatory T (Treg) cells, and CD45RA- Forkhead-Box-Protein P3low (FoxP3low) memory T cells were significantly increased in nasal polyps compared with PBMC. Conclusion In this study, we presented a detailed characterization of CD4+ and CD8+ T-cell subpopulations in patients with CRSwNP. CD8+ T cells were more prominent in nasal polyps than in CD4+ T cells. Both nasal CD8+ T cells and CD4+ T cells predominantly had an effector memory phenotype. Among CD4+ T cells, activated Treg cells were increased in nasal polyps compared with PBMC. The data point toward a local regulation of T-cell composition within the microenvironment of nasal polyps, which might be further exploited in the future to develop novel immunotherapeutic strategies.

scholarly journals Effect of Cyclophosphamide Treatment on Central and Effector Memory T Cells in Mice

2018 ◽  
Vol 37 (5) ◽  
pp. 373-382 ◽  
Author(s):  
Marcin Włodarczyk ◽  
Elżbieta Ograczyk ◽  
Magdalena Kowalewicz-Kulbat ◽  
Magdalena Druszczyńska ◽  
Wiesława Rudnicka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Immunosuppressive Agent ◽  
Central Memory ◽  
Effector Memory ◽  
Memory Cells ◽  
Memory T Cell ◽  
Effector Memory T Cells ◽  
The Impact

Immunological memory is a key feature of adaptive immunity. It provides the organism with long-lived and robust protection against infection. The important question is whether cyclophosphamide (CP), as immunosuppressive agent used in cancer therapy and in some autoimmune diseases, may act on the memory T-cell population. We investigated the effect of CP on the percentage of central memory T cells (TCM) and effector memory T cells (TEM) in the mouse model of CP-induced immunosuppression (8-10-week-old male C57BL/6 mice CP treated for 7 days at the daily dose of 50 μg/g body weight [bw], manifested the best immunosuppression status, as compared to lower doses of CP: 10 or 20 μg/g bw). The CP induced a significant decrease in the percentage of CD8+ (TCM), compared to nonimmunosuppressed mice. This effect was not observed in the case of CD4+ TCM population. The percentage of gated TEM with CD4 and CD8 phenotype was significantly decreased in CP-treated mice, as compared to the control ones. Taken together, the above data indicate that CP-induced immunosuppression in mice leads to a reduction in the abundance of central memory cells possessing preferentially CD8+ phenotype as well as to a reduction in the percentage of effector memory cells (splenocytes both CD4+ and CD8+), compared to the cells from nonimmunosuppressed mice. These findings in mice described in this article may contribute to the understanding of the complexity of the immunological responses in humans and extend research on the impact of the CP model of immunosuppression in mice and memory T-cell populations.

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