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 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.

Abnormalities of the Bone Marrow Immune Microenvironment in Patients with Prolonged Isolated Thrombocytopenia after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4602-4602
Author(s):  
Yang Song ◽  
Yuan Kong ◽  
Min-Min Shi ◽  
Yu-Qian Sun ◽  
Yu Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Microenvironment ◽  
Hematopoietic Stem ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Abstract Background:Prolonged Isolated Thrombocytopenia (PT), is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and defined as the engraftment of all peripheral blood cell lines other than a PLT count ≤20×10E+9/L or dependence on PLT transfusions for more than 90 days after allo-HSCT. Nevertheless, the mechanisms underlying PT remain unclear. Recent studies have presumed that the mechanism of PT might be similar, at least in part, to that of Immune Thrombocytopenia (ITP). BM immune microenvironment is considered to be involved in the regulation of hematopoiesis, and also influence the production of platelets. There is growing evidence that activated CD8+ T cells in the bone marrow (BM) of patients with ITP might suppress megakaryocyte apoptosis, leading to impaired platelet production. In our previous study, we also found the deregulated T cells responses in BM were associated with ITP patients. Therefore, we hypothesized aberrant immune microenvironment may also influence the production of platelet after allo-HSCT, contributing to the occurrence of PT, so we conducted a study to analyze the alteration of T cell subpopulations and cytokines in BM micro-environment of allotransplant patients. Aims:To compare the cellular compositions and function of T cells in BM microenvironment between patients with PT and good graft function (GGF) after allo-HSCT. Methods:Using a prospective nested case-control study, the T cell subpopulations in BM were analyzed by flow cytometry in 15 patients with PT, 30 matched patients with GGF after allo-HSCT, and 15 healthy donors (HDs). The fractions of T cells, including Th1, Tc1,Th2, Tc2 ,Th17 and Treg were identified as CD3+CD8-IFN-gama+, CD3+CD8-IFN-gama+, CD3+CD8+IL4+, CD3+CD8+IL-4+, CD3+CD8-IL17A+ and CD3+CD4+CD25+Foxp3+, respectively. The levels of IFN-gama, IL-4 and IL-17A in BM plasma were detected by cytometric beads assay. Results: The demographic and clinical characteristics were similar between allo-HSCT patients with PT and those with GGF. The T cell subset analysis revealed that the proportion of CD8+ T cells in BM was higher in PT patients. The in vitro cytokine stimulated tests demonstrated a significant higher proportion of Th1 in PT patients (29.8% ±13.0% vs. 21.7%±12.2%, P=0.01), and we also found an elevated percentage of Tc1 in PT patients when compared with GGF (39.3% ±19.3% vs. 23.0% ± 14.0%, P=0.01). Meanwhile, the similar percentage of Th2 and Tc2 were found in PT patients. The type-1/ type-2 response ratio was calculated by the percentages of Th1/Th2 and Tc1/Tc2. A significant elevation in the ratio of Tc1/Tc2 (37.3 vs. 22.1 vs. 15.6, P<0.05) was observed in PT when compared with those in GGF and HDs, whereas the ratio of Th1/Th2 did not differ from GGF. Moreover, we also found the significant elevated percentage of Th17 (3.1% ±2.1% vs. 1.1%± 0.7%, P<0.01) and the similar percentage of Treg in PT patients compared with GGF, leading to a higher ratio of Th17/Treg (0.9 vs. 0.6 vs. 0.3, P<0.05). The changes of IFN-gama, IL-4 and IL-17A levels in BM plasma detected by cytometric beads assay were in accordance with the intracellular cytokine results analyzed by flow cytometry. Summary/Conclusion: Our study demonstrated that the abnormal BM immune microenvironment including the higher percentage of Th1, Tc1, and Th17 cells in patients with PT, suggesting that the dysfunction of T cells response in BM immune microenvironment may contribute to the occurrence of PT after allo-HSCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of Vaccination on Distribution of T Cell Subsets in Antiretroviral-Treated HIV-Infected Children

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Premrutai Thitilertdecha ◽  
Ladawan Khowawisetsut ◽  
Palanee Ammaranond ◽  
Poonsin Poungpairoj ◽  
Varangkana Tantithavorn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Replication ◽  
Cd4 Count ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Influenza A H1n1 ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
The Impact

Antiretroviral therapy (ART) is generally prescribed to patients with human immunodeficiency virus (HIV) infection with vaccination introduced to prevent disease complications. However, little is known about the influence of immunization on T cell subsets’ distribution during the course of infection. This study aims to identify the impact of viral replication and immunization on naïve, effector, effector memory, and central memory T cell subpopulations in ART-treated HIV-infected children. Fifty patients were recruited and injected intramuscularly with influenza A (H1N1) 2009 vaccine on the day of enrollment (day 0) and day 28. Blood samples were collected for pre- and postvaccination on days 0 and 56 for analyzing T cell phenotypes by flow cytometry. Phenotypes of all T cell subsets remained the same after vaccination, except for a reduction in effector CD8+ T cells. Moreover, T cell subsets from patients with controllable viral load showed similar patterns to those with virological failure. Absolute CD4 count was also found to have a positive relationship with naïve CD4+ and CD8+ T cells. In conclusion, vaccination and viral replication have a little effect on the distribution of T cell subpopulations. The CD4 count can be used for prediction of naïve T cell level in HIV-infected patients responding to ART.

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 Identification of the Lymphoma-Initiating Cell Population in a T Cell Lymphoma Mouse Model Resembling Human Anaplastic Large Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2213-2213
Author(s):  
Cathrin Klingeberg ◽  
Stefanie Kreutmair ◽  
Cornelius Miething ◽  
Marie Follo ◽  
Christian Peschel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Double Negative ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Abstract In 60% of anaplastic large cell lymphoma (ALCL) patients a translocation t(2;5) (p23;q35) is found, which results in NPM-ALK fusion gene expression and constitutive activation of the ALK tyrosine kinase. Immunophenotypic characterization of human ALCLs revealed highly CD30-positive cells of T- or Null-cell-origin. However, the origin of the lymphoma initiating cell population as well as NPM-ALK signal transduction in course of the disease remains unclear. In this regard, we established a retroviral murine bone marrow transplantation model resembling human ALCL. Therefore we use an inducible Cre/loxP system where NPM-ALK expression is restricted to early T cells. We infected bone marrow of Lck-Cre transgenic mice with our MSCV-Stop-NPM-ALK-IRES-EGFP vector and transplanted it into lethally irradiated recipient mice. With a latency of 4-5 months, these mice developed Thy1.2-positive lymphomas and died from neoplastic T cell infiltration of bone marrow and lymphatic organs. Immunophenotypic analysis confirmed T cell origin of the lymphomas with the characteristic high CD30 expression. Staining of the T cell subpopulations demonstrated high NPM-ALK expression in immature CD4-/CD8- double negative T cells and undifferentiated CD4+/CD8+ double positive T cells. Interestingly, FACS-staining for the proliferation marker Ki-67 as well as the activation marker CD30 revealed highest expression in the CD4-/CD8- double negative T cells. Therefore we hypothesized that the lymphoma-initiating cell must be within this early T cell population. To substantiate our hypothesis we performed secondary transplantations with sorted T cell subpopulations and indeed, only the CD4-/CD8- double negative population was able to initiate T cell lymphoma in the recipient mice. Immunophenotypic characterization of the lymphoma population of these secondary transplanted mice revealed undifferentiated T cells of all CD4/CD8 subtypes, which argues for the existence of a lymphoma initiating cell population, which can still partly differentiate. Interestingly the CD4-/CD8- double negative lymphoma population aberrantly expressed the T cell receptor alpha/beta chain, which may allow these early T cells to establish a systemic lymphoma. Further analysis of the lymphoma population showed lymphatic precursors (CLP) as well as multipotent progenitors (MMP) and haematopoetic stem cells (LSK), which suggests early bone marrow or thymic progenitor cells as the pool of the lymphoma-initiating cell population. We therefore were able to prove the existence of lymphoma initiating stem cells in a highly relevant NPM-ALK positive CD30 expressing mouse model of ALCL. Further analysis will give insides into eradication of the identified lymphoma stem cell population by clinical relevant NPM-ALK inhibitors and CD30 immunotoxins. Disclosures No relevant conflicts of interest to declare.

scholarly journals Adult Renal Stem/Progenitor Cells Can Modulate T Regulatory Cells and Double Negative T Cells

2020 ◽  
Vol 22 (1) ◽  
pp. 274
Author(s):  
Claudia Curci ◽  
Angela Picerno ◽  
Nada Chaoul ◽  
Alessandra Stasi ◽  
Giuseppe De Palma ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Progenitor Cells ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Double Negative ◽  
Chronic Injury ◽  
Peripheral Blood Mononuclear ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Adult Renal Stem/Progenitor Cells (ARPCs) have been recently identified in the human kidney and several studies show their active role in kidney repair processes during acute or chronic injury. However, little is known about their immunomodulatory properties and their capacity to regulate specific T cell subpopulations. We co-cultured ARPCs activated by triggering Toll-Like Receptor 2 (TLR2) with human peripheral blood mononuclear cells for 5 days and 15 days and studied their immunomodulatory capacity on T cell subpopulations. We found that activated-ARPCs were able to decrease T cell proliferation but did not affect CD8+ and CD4+ T cells. Instead, Tregs and CD3+ CD4- CD8- double-negative (DN) T cells decreased after 5 days and increased after 15 days of co-culture. In addition, we found that PAI1, MCP1, GM-CSF, and CXCL1 were significantly expressed by TLR2-activated ARPCs alone and were up-regulated in T cells co-cultured with activated ARPCs. The exogenous cocktail of cytokines was able to reproduce the immunomodulatory effects of the co-culture with activated ARPCs. These data showed that ARPCs can regulate immune response by inducing Tregs and DN T cells cell modulation, which are involved in the balance between immune tolerance and autoimmunity.

scholarly journals Sympathetic Enhancement of Memory T-Cell Homing and Hypertension Sensitization

2020 ◽  
Vol 126 (6) ◽  
pp. 708-721 ◽  
Author(s):  
Liang Xiao ◽  
Luciana Simao do Carmo ◽  
Jason D. Foss ◽  
Wei Chen ◽  
David G. Harrison
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Sympathetic Nerves ◽  
Designer Drug ◽  
Effector Memory ◽  
Bone Marrow Niche ◽  
Sympathetic Outflow ◽  
Ang Ii ◽  
Cell Homing

Rationale: Effector memory T lymphocytes (T EM cells) exacerbate hypertension in response to repeated hypertensive stimuli. These cells reside in the bone marrow for prolonged periods and can be reactivated on reexposure to the hypertensive stimulus. Objective: Because hypertension is associated with increased sympathetic outflow to the bone marrow, we hypothesized that sympathetic nerves regulate accumulation and reactivation of bone marrow–residing hypertension-specific T EM cells. Methods and Results: Using unilateral superior cervical ganglionectomy in wild-type C57BL/6 mice, we showed that sympathetic nerves create a bone marrow environment that supports residence of hypertension-specific CD8 + T cells. These cells, defined by their proliferative response on coculture with dendritic cells from Ang (angiotensin) II–infused mice, were reduced in denervated compared with innervated bone of Ang II–infused mice. Adoptively transferred CD8 + T cells from Ang II–infused mice preferentially homed to innervated compared with denervated bone. In contrast, ovalbumin responsive T cells from OT-I mice did not exhibit this preferential homing. Increasing superior cervical ganglion activity by activating Gq-coupled designer receptor exclusively activated by designer drug augmented CD8 + T EM bone marrow accumulation. Adoptive transfer studies using mice lacking β2AR (β2 adrenergic receptors) indicate that β2AR in the bone marrow niche, rather than T-cell β2AR is critical for T EM cell homing. Inhibition of global sympathetic outflow using Gi-coupled DREADD (designer receptor exclusively activated by designer drug) injected into the rostral ventrolateral medulla or treatment with a β2AR antagonist reduced hypertension-specific CD8 + T EM cells in the bone marrow and reduced the hypertensive response to a subsequent response to low dose Ang II. Conclusions: Sympathetic nerves contribute to the homing and survival of hypertension-specific T EM cells in the bone marrow after they are formed in hypertension. Inhibition of sympathetic nerve activity and β2AR blockade reduces these cells and prevents the blood pressure elevation and renal inflammation on reexposure to hypertension stimuli.

scholarly journals Disproportion in T-cell subpopulations in immunodeficient mutant hr/hr mice.

1979 ◽  
Vol 149 (1) ◽  
pp. 228-233 ◽  
Author(s):  
A B Reske-Kunz ◽  
M P Scheid ◽  
E A Boyse
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Lymph Nodes ◽  
Salient Feature ◽  
Mutant Gene ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Mice of the HRS strain, which carry the mutant gene hr, were examined for abnormalities in representation of the three T-cell sets Ly1, Ly23, and Ly123 in the spleen. The salient feature of hr/hr mice, which are immunologically deficient, in comparison with +/hr segregants, was a gross disproportion in numbers of cells belonging to the Ly1 and Ly123 sets, at the age of 3--3.5 mo. At this age, Ly123 cells of hr/hr spleen outnumbered Ly1 cells by 2:1, whereas in +/hr spleens Ly123 cells were outnumbered by approximately 1:2. Cells from pooled lymph nodes of hr/hr mice did not show a correspondingly gross disporprotion of Ly1 and Ly123 cells. Total counts of splenic T cells, and of B cells, were not significantly different in hr/hr and +/hr mice.

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