The Regulatory Effects of mTOR Complexes in the Differentiation and Function of CD4+ T Cell Subsets

T cells are an important part of the adaptive immune system and play critical roles in the elimination of various pathogens. T cells could differentiate into distinct cellular subsets under different extracellular signals and then play different roles in maintaining host homeostasis and defense. The mechanistic target of rapamycin (mTOR) is a conserved intracellular serine/threonine kinase which belongs to the phosphoinositide 3-kinase- (PI3K-) related kinase family. The mTOR signaling pathway is closely involved in a variety of cell biological processes, including cell growth and cell metabolism, by senses and integrates various environmental cues. Recent studies showed that mTOR including mTORC1 and mTORC2 is closely involved in the development of T cell subpopulations such as Th1, Th2, Th9, Th17, follicular helper T cells (Tfh), and Treg cells through distinctive pathways. We herein mainly focused on the recent progress in understanding the roles of mTOR in regulating the development and differentiation of CD4+ T cell subsets.

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Effects of Telbivudine Treatment on the Circulating CD4+T-Cell Subpopulations in Chronic Hepatitis B Patients

Mediators of Inflammation ◽

10.1155/2012/789859 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 18

Author(s):

Yanhua Zheng ◽

Zemin Huang ◽

Xianhua Chen ◽

Yi Tian ◽

Jun Tang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hepatitis B ◽

Antiviral Agents ◽

Adaptive Immune Response ◽

Treg Cells ◽

T Cell Subsets ◽

Th2 Cells ◽

Th1 Cell ◽

T Cell Subpopulations

CD4+T cells serve as master regulators of the adaptive immune response to HBV. However, CD4+T-cell subsets are heterogeneous, and it remains unknown how the antiviral agents affect the different CD4+T cell subtypes. To this end, the expressions of signature transcription factors and cytokines of CD4+T-cell subtypes were examined in hepatitis B patients before and after treatment with telbivudine. Results showed that, upon the rapid HBV copy decrease induced by telbivudine treatment, the frequencies and related cytokines of Th17 and Treg cells were dramatically decreased, while those for Th2 cells were dramatically increased. No obvious changes were observed in Th1 cell frequencies; although, IFN-γexpression was upregulated in response to telbivudine treatment, suggesting another cell source of IFN-γin CHB patients. Statistical analyses indicated that Th17 and Tr1 (a Treg subtype) cells were the most sensitive subpopulations of the peripheral blood CD4+T cells to telbivudine treatment over 52 weeks. Thus, Th17 and Tr1 cells may represent a suitable and effective predictor of responsiveness during telbivudine therapy. These findings not only improve our understanding of hepatitis pathogenesis but also can aid in future development of appropriate therapeutic strategies to control viral hepatitis.

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Decreased numbers and sex-based differences of circulating regulatory T cells in patients with seropositive undifferentiated arthritis

Therapeutic Advances in Chronic Disease ◽

10.1177/2040622320986721 ◽

2021 ◽

Vol 12 ◽

pp. 204062232098672

Author(s):

Hong-Qing Niu ◽

Chenrui Yuan ◽

Chenglan Yan ◽

Na Li ◽

Yuan-Sheng Lei ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Flow Cytometric Analysis ◽

Treg Cells ◽

T Cell Subsets ◽

Joint Disease ◽

Healthy Controls ◽

Undifferentiated Arthritis ◽

Cell Subpopulations ◽

T Cell Subpopulations

Aims: CD4+ T cells play crucial roles as both mediators and regulators of the pathogenesis of rheumatoid arthritis (RA). However, the characteristics of CD4+ T cell subpopulations in the earliest stage of RA development remain unclear. Hence, we determined the proportions and absolute counts of circulating CD4+ T cell subsets in patients with seropositive undifferentiated arthritis (SUA), the early and preclinical stage of RA. Methods: Peripheral blood samples and clinical information were collected from 177 patients with SUA, 104 patients with RA, and 120 healthy controls. All patients were newly diagnosed and untreated. Proportions and absolute counts of CD4+ T cell subpopulations were determined by flow cytometric analysis. Results: In patients with SUA, percentages and absolute counts of circulating regulatory T (Treg) cells were decreased significantly and Th17/Treg cell ratios were abnormally increased, whereas Th17 cell numbers were similar to those in healthy controls. In addition, sex-based differences in circulating Treg cells were observed, with female SUA patients having lower proportions and absolute counts of Treg cells than those in males. Moreover, female patients with SUA had higher erythrocyte sedimentation rates and 28-joint Disease Activity Scores than those in males. Conclusion: Immune tolerance deficiency resulting from an abnormal reduction in circulating Treg cells might be the most crucial immunological event in the earliest stage of RA. The sex-specific disparity in Treg cells should also be considered for immunoregulatory and preventive strategies targeting early RA.

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Functionally specialized human CD4+ T-cell subsets express physicochemically distinct TCRs

eLife ◽

10.7554/elife.57063 ◽

2020 ◽

Vol 9 ◽

Author(s):

Sofya A Kasatskaya ◽

Kristin Ladell ◽

Evgeniy S Egorov ◽

Kelly L Miners ◽

Alexey N Davydov ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptors ◽

Adaptive Immune System ◽

T Cell Subsets ◽

Effector Memory ◽

Intrinsic Properties ◽

Antigen Specificity ◽

Adaptive Immune ◽

Transition Pathways

The organizational integrity of the adaptive immune system is determined by functionally discrete subsets of CD4+ T cells, but it has remained unclear to what extent lineage choice is influenced by clonotypically expressed T-cell receptors (TCRs). To address this issue, we used a high-throughput approach to profile the αβ TCR repertoires of human naive and effector/memory CD4+ T-cell subsets, irrespective of antigen specificity. Highly conserved physicochemical and recombinatorial features were encoded on a subset-specific basis in the effector/memory compartment. Clonal tracking further identified forbidden and permitted transition pathways, mapping effector/memory subsets related by interconversion or ontogeny. Public sequences were largely confined to particular effector/memory subsets, including regulatory T cells (Tregs), which also displayed hardwired repertoire features in the naive compartment. Accordingly, these cumulative repertoire portraits establish a link between clonotype fate decisions in the complex world of CD4+ T cells and the intrinsic properties of somatically rearranged TCRs.

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CD4+ Foxp3+ regulatory T cell-mediated immunomodulation by anti-depressants inhibiting acid sphingomyelinase

Biological Chemistry ◽

10.1515/hsz-2018-0159 ◽

2018 ◽

Vol 399 (10) ◽

pp. 1175-1182 ◽

Cited By ~ 6

Author(s):

Jürgen Schneider-Schaulies ◽

Niklas Beyersdorf

Keyword(s):

T Cells ◽

T Cell ◽

Treg Cells ◽

Tricyclic Antidepressant ◽

Acid Sphingomyelinase ◽

Human T Cells ◽

And Function ◽

Rate Limiting ◽

Deficient Mice

AbstractAcid sphingomyelinase (ASM) is the rate-limiting enzyme cleaving sphingomyelin into ceramide and phosphorylcholin. CD4+Foxp3+regulatory T (Treg) cells depend on CD28 signaling for their survival and function, a receptor that activates the ASM. Both, basal and CD28-induced ASM activities are higher in Treg cells than in conventional CD4+T (Tconv) cells. In ASM-deficient (Smpd1−/−) as compared to wt mice, membranes of T cells contain 7–10-fold more sphingomyelin and two- to three-fold more ceramide, and are in a state of higher order than membranes of T cells from wt mice, which may facilitate their activation. Indeed, the frequency of Treg cells among CD4+T cells in ASM-deficient mice and their suppressive activityin vitroare increased. Moreover,in vitrostimulation of ASM-deficient T cells in the presence of TGF-β and IL-2 leads to higher numbers of induced Treg cells. Pharmacological inhibition of the ASM with a clinically used tricyclic antidepressant such as amitriptyline in mice or in tissue culture of murine or human T cells induces higher frequencies of Treg cells among CD4+T cells within a few days. This fast alteration of the balance between T cell populationsin vitrois due to the elevated cell death of Tconv cells and protection of the CD25highTreg cells by IL-2. Together, these findings suggest that ASM-inhibiting antidepressants, including a fraction of the serotonin re-uptake inhibitors (SSRIs), are moderately immunosuppressive and should be considered for the therapy of inflammatory and autoimmune disorders.

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T Regulatory Cell Activation Exists in Pathogenesis of Polycythaemia Vera.

Blood ◽

10.1182/blood.v110.11.4642.4642 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4642-4642

Author(s):

Xin Wang ◽

Wenbo Zhao ◽

Yanxia Liu ◽

Ying Li

Keyword(s):

T Cells ◽

T Cell ◽

Peripheral Blood ◽

Protein Level ◽

Treg Cells ◽

T Cell Immunity ◽

Polycythaemia Vera ◽

Cell Immunity ◽

And Function ◽

Hematopoietic Activity

Abstract Polycythaemia vera (PV) is a clonal disorder arising from a pluripotent hematopoietic progenitor cell. The etiology of PV remains unknown and there is no consensus as to the optimal therapy for this disorder. T regulatory (Treg) cells play a vital role in the maintenance of self-tolerance, control of auto-immunity and regulation of T-cell homeostasis, and they modulate overall immune responses against a variety of pathogens. Recent studies revealed that Treg cells play a crucial role in the process of hematopoietic activity. However, the effect of Treg cells in PV has not been reported. The Treg cells might participate in the dysfunction of T-cell immunity in PV. The profile and function of Treg cells in PV patients were explored in this study. Peripheral blood was withdrawn from 21 PV patients (Female 8 ; Male 13), as well as 25 age-matched healthy donors (F 9 ; M 16) as controls. All samples were taken after informed consent and collected from PV patients prior to treatment. Diagnoses of PV were made according to clinical and laboratory criteria. The peripheral blood mononuclear cells (PBMCs) were subjected to flow cytometry analyses after labeling with anti-CD4, anti-CD25, and anti-Foxp3 antibodies. Real-time PCR and Western blotting were also performed to identify quantitative FOXP3 mRNA expression and protein level in the PBMCs from PV in comparison to controls. The relationships between the percentage of Treg cells, the expressions for quantitative mRNA and protein, with the clinical data were assessed. The percentage of CD4+ T-cells was significant decreased in the group of PV than in normal control (28.7±7.07% vs 38.6±8.38%, p<0.05). But the percentage of CD4+CD25+FOXP3+ T-cells (Treg cells) in PV patients was significantly increased when compared to the control (10.93±4.02% vs 5.86±1.99%, p<0.05). Moreover, the quantitative mRNA expression of FOXP3 (64.23±18.52 vs 16.06±4.78, p<0.05) and protein expression of FOXP3 (0.74±0.16 vs 0.62±0.10, p<0.05)) were significantly enhanced in PV patients (shown in Figure 1). In conclusion, we showed that patients with PV have enhanced percentage of Treg cells in their peripheral blood. This was substantiated further with the finding that overexpressions of FOXP3 in PV both in mRNA and protein level. These results highlight important Treg-cell abnormalities in patients with PV because natural Treg cells are significantly increased in number and function. The underlying mechanism is still undefined, but the increased frequency and function of Treg cells might account for the abnormal T cell immunity in PV patients. It was suggested that there may be differently suppressive machanisms for Treg in these patients. The elevated Treg cells in PV might be activated and then affect the hematopoietic activity. We believe that Treg cells might involved in the dysfunction of T/NK cells in their disability to downregulate the hematopoietic proliferation in PV. And the expansion of Treg cells may be a feature of PV and associated with the pathogenesis of PV. Further investigation in this abnormality might provide novel therapy clue for this disease. Figure Figure

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Function and expression of checkpoint inhibitors and immune agonists on immune cells in monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and MM and tumor-specific T lymphocytes.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.11577 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 11577-11577 ◽

Cited By ~ 1

Author(s):

Jooeun Bae ◽

Brandon Nguyen ◽

Yu-Tzu Tai ◽

Teru Hideshima ◽

Dharminder Chauhan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Suppressor Cells ◽

Treg Cells ◽

T Cell Subsets ◽

Direct Stimulation ◽

Novel Therapeutic Strategies

11577 Background: Characterization of expression and function of immune regulatory molecules in tumor microenvironment will provide the framework for developing novel therapeutic strategies. Methods: We evaluated the expression and functional impact of various immuno-regulatory molecules, PD-1, PDL-1, PDL-2, LAG3, TIM3, OX40 and GITR, on the CD138+ tumor cells, myeloid derived suppressor cells (MDSC), and T cell subsets from patients with MGUS, SMM and active MM (newly diagnosed, relapsed, relapsed/refractory), and the myeloma-specific cytotoxic T lymphocytes (CTL) induced with XBP1/CD138/CS1 peptides. Results: PDL-1/PDL-2 was more highly expressed on CD138+ myeloma cells in active MM than SMM or MGUS. G-type MDSC (CD11b+CD33+HLA-DRlowCD15+). Treg cells (CD3+CD4+/CD25+FOXP3+) numbers were increased and expressed higher levels of PD1/PD-L1 in active MM than in MGUS, SMM or healthy donors. Among the checkpoint molecules (PD-1, PDL-1, PDL-2, LAG3, OX40, GITR) evaluated, PD-1 showed the highest expression on CD3+CD4+ and CD3+CD8+T cells in BMMC and PBMC from patients with active MM. Functionally, T cells from MM patients showed increased proliferation upon treatment with an individual immune agonist ( > 150%) or checkpoint inhibitor ( > 100%). Interestingly, each individual anti-checkpoint molecule induced proliferation of T cells expressing other checkpoint molecules. In addition, the blockade of PD1, LAG3 or TIM3 enhanced MM antigen-specific cytotoxicity, assessed by parameters including CD107a, granzyme B and IFN-g production, which was most prominent within the memory CTL subset of MM antigen-specific T cells. Conclusions: These results demonstrate an increased frequency of immune regulatory cells, which highly express checkpoint inhibitors in active MM. Direct stimulation with an immune agonist or blockade of a checkpoint inhibitor increased MM patients’ T cell proliferation and myeloma-specific CTL function, supporting development of combination immune regulatory therapies to improve patient outcome in MM.

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Increased Activation and Oligoclonality of Peripheral CD8+ T Cells in the Chronic Human Helminth Infection Alveolar Echinococcosis

Infection and Immunity ◽

10.1128/iai.70.3.1168-1174.2002 ◽

2002 ◽

Vol 70 (3) ◽

pp. 1168-1174 ◽

Cited By ~ 21

Author(s):

Burkhard J. Manfras ◽

Stefan Reuter ◽

Thomas Wendland ◽

Peter Kern

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Alveolar Echinococcosis ◽

Ex Vivo ◽

Active Role ◽

Cell Receptor ◽

T Cell Subsets ◽

And Function

ABSTRACT Alveolar echinococcosis (AE) in humans is a chronic disease characterized by slowly expanding liver lesions. Cellular immunity restricts the spreading of the extracellular pathogen, but functional contributions of CD4+ and CD8+ T cells are not defined. Here we studied ex vivo the phenotype and function of circulating T-cell subsets in AE patients by means of flow cytometry, T-cell receptor spectratyping, and lymphocyte proliferation. AE patients with parasitic lesions displayed a significant increase of activation of predominantly CD8+ T cells compared to healthy controls and AE patients without lesions. In vitro, proliferative T-cell responses to polyclonal stimulation with recall antigens and Echinococcus multilocularis vesicular fluid antigen were sustained during chronic persisting infection in all AE patients. Only in AE patients with parasitic lesions did T-cell receptor spectratyping reveal increased oligoclonality of CD8+ but not CD4+ T cells, suggesting a persistent antigenic drive for CD8+ T cells with subsequent proliferation of selected clonotypes. Thus, our data provide strong evidence for an active role of CD8+ T cells in AE.

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Early Thymectomy Is Associated With Long-Term Impairment of the Immune System: A Systematic Review

Frontiers in Immunology ◽

10.3389/fimmu.2021.774780 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nara Vasconcelos Cavalcanti ◽

Patrícia Palmeira ◽

Marcelo Biscegli Jatene ◽

Mayra de Barros Dorna ◽

Magda Carneiro-Sampaio

Keyword(s):

Systematic Review ◽

T Cells ◽

Immune System ◽

T Cell ◽

Heart Diseases ◽

Subsequent Development ◽

Treg Cells ◽

Ki 67 ◽

T Cell Subpopulations

Background and AimsCongenital heart diseases (CHDs) are diagnosed in approximately 9 in 1,000 newborns, and early cardiac corrective surgery often requires partial or complete thymectomy. As the long-term effect of early thymectomy on the subsequent development of the immune system in humans has not been completely elucidated, the present study aimed to evaluate the effects of thymus removal on the functional capacity of the immune system after different periods.MethodsA systematic review of the literature was performed using MEDLINE, EMBASE, LILACS and Scopus. The inclusion criteria were original studies that analyzed any component of the immune system in patients with CHD who had undergone thymectomy during cardiac surgery in the first years of life. The results were evaluated for the quality of evidence.ResultsTwenty-three studies were selected and showed that patients who underwent a thymectomy in the first years of life tended to exhibit important alterations in the T cell compartment, such as fewer total T cells, CD4+, CD8+, naïve and CD31+ T cells, lower TRECs, decreased diversity of the TCR repertoire and higher peripheral proliferation (increased Ki-67 expression) than controls. However, the numbers of memory T cells and Treg cells differed across the selected studies.ConclusionsEarly thymectomy, either partial or complete, may be associated with a reduction in many T cell subpopulations and TCR diversity, and these alterations may persist during long-term follow-up. Alternative solutions should be studied, either in the operative technique with partial preservation of the thymus or through the autograft of fragments of the gland.Systematic Review RegistrationProspero [157188].

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T Cell Metabolism and Memory

Blood ◽

10.1182/blood-2018-99-109535 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. SCI-6-SCI-6

Author(s):

Jeffrey C Rathmell

Keyword(s):

T Cells ◽

T Cell ◽

Glucose Transporter ◽

Cell Metabolism ◽

Effector Function ◽

Glutamine Metabolism ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Th1 Cells ◽

Inflammatory Models

Abstract Lymphocyte activation leads to rapid proliferation and differentiation and we have shown that CD4 T cell subsets are metabolically distinct. These specific metabolic programs may allow new understanding and approaches to manipulate immunity. Using metabolic network analysis of metabolomics and proteomics we defined several metabolic nodes differentially utilized by CD4 T cell subsets, including glutamine metabolism. By genetically deleting the glucose transporter Glut1 or the glutaminolysis enzyme, Glutaminase (GLS), we have shown that glycolysis and glutaminolysis are both used by activated T cells. All effector T cells require glycolysis, but we found that Th17 cells preferentially require GLS while Th1 cells are actively impaired by this enzyme. Thus, inhibition of GLS both reduces Th17 responses and promotes differentiation of Th1 cells and can lead to signs of T cell exhaustion. We show that GLS-deficiency can protect against Th17-mediated inflammatory models and also can augment effector function of Th1 CAR-T cells against B cell targets. Understanding mechanisms that regulate T cell metabolism may provide new tools to modulate immunity the balance of T cell effector populations to both suppress inflammation or promote effector function. Disclosures Rathmell: Calithera: Research Funding.

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Tigit Expression Defines a Subset of Activated Treg Cells with Prognostic Relevance in Follicular Lymphoma

Blood ◽

10.1182/blood-2018-99-115328 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1590-1590 ◽

Cited By ~ 1

Author(s):

Zhi-Zhang Yang ◽

Hyo Jin Kim ◽

Shahrzad Jalali ◽

Hongyan Wu ◽

Tammy Price-Troska ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Follicular Lymphoma ◽

Research Funding ◽

Memory T Cells ◽

Treg Cells ◽

T Cell Subsets ◽

Effector Memory ◽

Cell Numbers ◽

Treg Subset

Abstract T cell Ig and ITIM domain (TIGIT) is an immune checkpoint molecule that is expressed on a variety of cell types including NK cells, effector and memory T cells, and Treg cells. Upon ligation with CD155, TIGIT delivers an inhibitory signal and negatively regulates anti-tumor responses. While important in normal T-cell biology, the pathological significance of TIGIT expression and function in the tumor microenvironment of the patients with follicular lymphoma (FL) is largely unknown. The present study sought to phenotypically and functionally characterize TIGIT+ T cell subsets in FL. While its expression is not detected on resting T cells in peripheral blood, we found that TIGIT is highly expressed on intratumoral T cells from FL. Treatment with cytokines such as IL-4 and TGF-β downregulated TIGIT expression on T cells. We found that TIGIT is predominantly expressed on effector memory T cells (TEM) with an activation/exhausted phenotype, and TIGIT+ T cells have higher expression levels of CD69 and PD-1 when compared to TIGIT- T cells. Functionally, TIGIT+ T cells displayed reduced capacity of cell proliferation and cytokine production (IFN-γ and IL-2). Using mass cytometry (CyTOF), we observed that TIGIT is abundantly expressed on some intratumoral Treg (CD4+CD25+Foxp3+) cells, while other Treg cells lack TIGIT expression in FL, forming two subsets of Treg cells: CD4+CD25+TIGIT+ and CD4+CD25+TIGIT-. These two subsets are phenotypically distinct in that CD25+TIGIT+ cells exhibited increased expression of activation/costimulatory markers such as CD69, CD27 and CD28 compared to CD25+TIGIT-, suggesting an activated Treg subset of CD25+TIGIT+ cells. This CD25+TIGIT+ subset had increased suppressive function and could more effectively inhibit activation and proliferation of CD8+ T cells than CD25+TIGIT- cells. Furthermore, we found that lymphoma B cells promoted the development of TIGIT-expressing T cells as TGF-β-mediated downregulation of TIGIT on T cells was inhibited when CD19+ lymphoma cells were present. Using a cohort of 31 FL patients, we found that intratumoral TIGIT-expressing T cells were associated with a favorable prognosis. Patients with TIGIT+ T cell numbers greater than 50% had better overall survival than patients with TIGIT+ T cell numbers less than 50%. Taken together, our results reveal a role of TIGIT in defining Treg cell subsets with different immune function and TIGIT expression may be useful in predicting patient outcome in FL. Disclosures Ansell: Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Merck & Co: Research Funding.

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