scholarly journals A novel α/β T-cell subpopulation defined by recognition of EPCR

2021 ◽  
Author(s):  
Elena Erausquin Arrondo ◽  
Maria Moran-Garrido ◽  
Jorge Saiz ◽  
Coral Barbas ◽  
Maria Gilda Dichiara Rodriguez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Peripheral Blood ◽  
Average Frequency ◽  
Lipid Binding ◽  
T Cell Subsets ◽  
Cell Subpopulation ◽  
Endothelial Protein C Receptor ◽  
Autoreactive T Cell ◽  
Self Recognition

T-cell self-recognition of antigen presenting molecules is led by antigen-dependent or independent mechanisms. The endothelial protein C receptor (EPCR) shares remarkable similarity with CD1d, including a lipid binding cavity. We identified EPCR-specific α/β T-cells in human peripheral blood of healthy donors. The average frequency in the CD3+ leukocyte pool is comparable to other autoreactive T-cell subsets that specifically bind MHC-like receptors. Alteration of the EPCR lipid cargo, revealed by X-ray diffraction studies, points to a prevalent, yet not exclusive, lipid-independent self-recognition. In addition, we solve the EPCR lipidome, and detect species not yet described as EPCR ligands. These studies report, for the first time, novel recognition by circulating α/β T-cells and provide grounds for EPCR and lipid mediated T-cell restriction.

Age-related increase of frequency of a new, phenotypically distinct subpopulation of human peripheral blood T cells expressing lowered levels of CD4

Blood ◽  
2001 ◽  
Vol 98 (4) ◽  
pp. 1100-1107 ◽  
Author(s):  
Ewa Bryl ◽  
Magdalena Gazda ◽  
Jerzy Foerster ◽  
Jacek M. Witkowski
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Human Peripheral Blood ◽  
The Elderly ◽  
Cell Subpopulation ◽  
Cell Phenotype ◽  
Receptor Complexes ◽  
Age Related

Aging is associated with modifications of T-cell phenotype and function, leading to impaired activation in response to both new and recall antigens. It is not known if T-cell activation results in elimination of a number of the CD4 molecules from the cell surface, as is the case with CD3/T-cell receptor complexes, or how aging influences the process. The T cells of young and elderly donors with reduced expression of CD4 were examined to see whether these cells exhibit other phenotypic features suggesting their active state. It was found that T lymphocytes expressing CD4 can be divided into 2 semidiscrete subpopulations: the major (CD4+) population, in which the level of expression of CD4 is constant and high, and a minor population (CD4lo), in which the expression of CD4 can be up to an order of magnitude lower than on the CD4+ cells. The proportion of CD4locells is age dependent and highly variable in the apparently healthy human population, with the expression of CD4 ranging from around 10% of all peripheral blood lymphocytes in the young to more than 30% in the elderly. Lowered expression of CD4 is correlated with a reduced expression of CD3, as well as with a decreased amount of CD28 and CD95Fas. Activation of CD4lo cells is suggested by their expression of CD25 and increased amounts of HLA-DR. Phenotypic characteristics of the CD4lo T-cell subpopulation suggest that it might be formed by (perhaps chronically) activated, temporarily apoptosis-resistant cells, possibly accumulating in the elderly.

scholarly journals Autoreactive CD1b-restricted T cells: a new innate-like T-cell population that contributes to immunity against infection

Blood ◽  
2011 ◽  
Vol 118 (14) ◽  
pp. 3870-3878 ◽  
Author(s):  
Sha Li ◽  
Hak-Jong Choi ◽  
Kyrie Felio ◽  
Chyung-Ru Wang
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Subsets ◽  
Autoreactive T Cell ◽  
Suitable Animal Model ◽  
Lipid Antigen ◽  
Listeria Infection ◽  
Express Group ◽  
Group 1

Abstract Group 1 CD1 (CD1a, -b, and -c) presents self and foreign lipid antigens to multiple T-cell subsets in humans. However, in the absence of a suitable animal model, the specific functions and developmental requirements of these T cells remain unknown. To study group 1 CD1-restricted T cells in vivo, we generated double transgenic mice (HJ1Tg/hCD1Tg) that express group 1 CD1 molecules in a similar pattern to that observed in humans (hCD1Tg) as well as a TCR derived from a CD1b-autoreactive T-cell line (HJ1Tg). Using this model, we found that similar to CD1d-restricted NKT cells, HJ1 T cells exhibit an activated phenotype (CD44hiCD69+CD122+) and a subset of HJ1 T cells expresses NK1.1 and is selected by CD1b-expressing hematopoietic cells. HJ1 T cells secrete proinflammatory cytokines in response to stimulation with CD1b-expressing dendritic cells derived from humans as well as hCD1Tg mice, suggesting that they recognize species conserved self-lipid antigen(s). Importantly, this basal autoreactivity is enhanced by TLR-mediated signaling and HJ1 T cells can be activated and confer protection against Listeria infection. Taken together, our data indicate that CD1b-autoreactive T cells, unlike mycobacterial lipid antigen-specific T cells, are innate-like T cells that may contribute to early anti-microbial host defense.

scholarly journals TCR repertoire analysis reveals effector memory T cells differentiation into Th17 cells in rheumatoid arthritis

2019 ◽  
Author(s):  
Xu Jiang ◽  
Shi-yu Wang ◽  
Chen Zhou ◽  
Jing-hua Wu ◽  
Yu-hao Jiao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Th17 Cells ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Systemic Autoimmune Disease ◽  
Autoreactive T Cell

AbstractThe pathogenesis of rheumatoid arthritis (RA), a systemic autoimmune disease characterized by autoreactive T-cell accumulation and pro-inflammatory cytokine overproduction, is unclear. Systematically addressing T-cell receptor (TCR) repertoires of different CD4+ T-cell subsets could help understand RA pathogenesis. Here, peripheral CD4+ T cells from treatment-naïve RA patients and healthy controls were sorted into seven subsets including naïve, effector, central memory, effector memory (EMT), Th1, Th17, and regulatory T cells. T-cell receptor β chain repertoires were then analyzed by next-generation sequencing. We identified T-cell clonal expansion in EMT and Th17 cells, with highly similar TCR repertoires between them. Ex vivo experiments demonstrated the preferred differentiation from EMT to Th17 cells in RA. Moreover, TCR diversity in subsets including Th17 was negatively correlated with RA disease activity indices such as C-reactive protein and erythrocyte sedimentation rate. Thus, shared and abnormally expanded EMT and Th17 TCR repertoires might be pivotal for RA pathogenesis.

scholarly journals Re-investigation of classic T cell subsets and identification of novel cell subpopulations by single-cell RNA sequencing

2021 ◽  
Author(s):  
Xuefei Wang ◽  
Xiangru Shen ◽  
Shan Chen ◽  
Hongyi Liu ◽  
Ni Hong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Single Cell ◽  
Rna Sequencing ◽  
T Cell Activation ◽  
Expression Profiles ◽  
T Cell Subsets ◽  
Cell Subpopulation ◽  
Single Cell Rna Sequencing

AbstractClassic T cell subsets are defined by a small set of cell surface markers, while single cell RNA sequencing (scRNA-seq) clusters cells using genome-wide gene expression profiles. The relationship between scRNA-seq Clustered-Populations (scCPops) and cell surface marker-defined classic T cell subsets remain unclear. Here, we interrogated 6 bead-enriched T cell subsets with 62,235 single cell transcriptomes and re-grouped them into 9 scCPops. Bead-enriched CD4 Naïve and CD8 Naïve were mainly clustered into their scCPop counterparts, while cells from the other T cell subsets were assigned to multiple scCPops including mucosal-associated invariant T cells and natural killer T cells. The multiple T cell subsets that form a single scCPop exhibited similar expression pattern, but not vice versa, indicating scCPops are much homogeneous cell populations with similar cell states. Interestingly, we discovered and named IFNhi T, a new T cell subpopulation that highly expressed Interferon Signaling Associated Genes (ISAGs). We further enriched IFNhi T by FACS sorting of BST2 for scRNA-seq analyses. IFNhi T cluster disappeared on tSNE plot after removing ISAGs, while IFNhi T cluster showed up by tSNE analyses of ISAGs alone, indicating ISAGs are the major contributor of IFNhi T cluster. BST2+ T cells and BST2− T cells showing different efficiencies of T cell activation indicates high level of ISAGs may contribute to quick immune responses.

scholarly journals Antigen exposure shapes the ratio between antigen-specific Tregs and conventional T cells in human peripheral blood

2016 ◽  
Vol 113 (41) ◽  
pp. E6192-E6198 ◽  
Author(s):  
Laura F. Su ◽  
Daniel del Alcazar ◽  
Erietta Stelekati ◽  
E. John Wherry ◽  
Mark M. Davis
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Ex Vivo ◽  
Human Peripheral Blood ◽  
T Cell Subsets ◽  
Major Influence ◽  
Cell Phenotype ◽  
Antigen Specificity ◽  
Cell Repertoire

The T-cell receptor (TCR) is required for maturation and function of regulatory T cells (Tregs), but the ligand specificities of Tregs outside the context of transgenic TCRs are largely unknown. Using peptide–MHC tetramers, we isolated rare specific Foxp3+ cells directly ex vivo from adult peripheral blood and defined their frequency and phenotype. We find that a proportion of circulating Tregs recognize foreign antigens and the frequency of these cells are similar to that of self-reactive Tregs in the absence of cognate infection. In contrast, the frequencies of Tregs that recognize some common microbial antigens are significantly reduced in the blood of most adults. Exposure to peripheral antigens likely has a major influence on the balance between Tregs and conventional T-cell subsets because a larger proportion of flu-specific T cells has a regulatory cell phenotype in the cord blood. Consistent with this finding, we show that lymphocytic choriomeningitis virus infection can directly modulate the ratio of virus-specific effectors and Tregs in mice. The resulting change in the balance within an antigen-specific T-cell population further correlates with the magnitude of effector response and the chronicity of infection. Taken together, our data highlight the importance of antigen specificity in the functional dynamics of the T-cell repertoire. Each specific population of CD4+ T cells in human peripheral blood contains a subset of Tregs at birth, but the balance between regulatory and effector subsets changes in response to peripheral antigen exposure and this could impact the robustness of antipathogen immunity.

Plasticity of human Th17 cells and iTregs is orchestrated by different subsets of myeloid cells

Blood ◽  
2011 ◽  
Vol 117 (24) ◽  
pp. 6532-6541 ◽  
Author(s):  
Bastian Hoechst ◽  
Jaba Gamrekelashvili ◽  
Michael P. Manns ◽  
Tim F. Greten ◽  
Firouzeh Korangy
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Human Peripheral Blood ◽  
Myeloid Cells ◽  
T Cell Subsets ◽  
T Helper ◽  
Hla Dr

Abstract CD4+ T helper cell differentiation is essential for mounting robust immune responses without compromising unresponsiveness toward self-tissue. Here, we show that different subsets of myeloid cells isolated from human peripheral blood modulate TGF-β–dependent CD4+ T-cell developmental programs ex vivo. Human CD14+HLA-DR−/low myeloid-derived suppressor cells (MDSCs) induce Foxp3+ regulatory T cells, whereas CD14+HLA-DR+ monocytes promote generation of IL-17–secreting RORc+ Th17 cells when cocultured with naive CD4+ T cells. More importantly, not only do these 2 subsets modulate the de novo induction of Tregs and Th17 cells from CD4+ T cells, but MDSCs also catalyze the transdifferentiation of Foxp3+ regulatory T cells from monocyte-induced Th17 cells. The mechanism of such Th17 plasticity is dependent on MDSC-derived TGF-β and retinoic acid. Our results identify a previously unknown feature of the different subsets of CD14+ myeloid cells namely their pivotal role in immune response regulation and plasticity of CD4+ T helper cells. We propose that different subsets of myeloid cells in humans can orchestrate the differentiation of naive CD4+ T cells into effector/regulatory T-cell subsets. The balance between these 2 subsets can impact the outcome of immune reaction from inflammation to tolerance.

scholarly journals Immunoregulatory T cell circuits in man. Alloantigen-primed inducer T cells activate alloantigen-specific suppressor T cells in the absence of the initial antigenic stimulus.

1983 ◽  
Vol 158 (1) ◽  
pp. 159-173 ◽  
Author(s):  
N K Damle ◽  
E G Engleman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Peripheral Blood ◽  
Cytotoxic T Cells ◽  
Suppressor Cells ◽  
Suppressive Effect ◽  
Third Party ◽  
T Cell Subsets ◽  
Suppressor T Cells ◽  
Specific Suppressor T Cells

Although alloantigen-specific suppressor T cells are generated in MLR, the cellular signals that lead to activation of suppressor T cells as opposed to cytotoxic T cells are unknown. The current study was undertaken to characterize interactions among T cell subsets involved in the generation of suppressor T cells in MLR. Human peripheral blood Leu-2+ (suppressor/cytotoxic) and Leu-3+ (helper/inducer) T cell subsets were activated with allogeneic non-T cells and then examined for their inductive effects on fresh autologous T cells. Fresh Leu-2+ cells proliferated in response to alloantigen-primed Leu-3+ cells and subsequently suppressed the response of fresh autologous Leu-3+ cells to the original, but not third party, allogeneic stimulator non-T cells. Moreover, only Leu-2+ cells that lacked the 9.3 marker, an antigen present on the majority of T cells including precursors of cytotoxic T cells, differentiated into suppressor cells. The alloantigen-specific suppressive effect of Leu-2+,9.3-cells was not mediated by cytolysis of allogeneic stimulator cells, nor could it be explained by alteration of MLR kinetics. Suppression was observed only when activated Leu-2+ cells were added to fresh MLRs within 24 h of initiation of cultures, suggesting that these cells block an early phase of the activation of Leu-3+ cells in MLR. These results indicate that alloantigen-primed inducer T cells can activate alloantigen-specific suppressor T cells in the absence of allogeneic stimulator cells.

Expansion of CD8+/perforin+ T-Cell Subset in Patients Predicts Response to Cyclosporin A Therapy in Patients with Erythroid Hypoplasia/Aplasia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1337-1337
Author(s):  
Hideaki Nitta ◽  
Yuka Harada ◽  
Hideo Hyodo ◽  
Akiro Kimura ◽  
Hironori Harada
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cyclosporin A ◽  
Aplastic Anemia ◽  
Cell Subset ◽  
T Cell Subsets ◽  
Cell Subpopulation ◽  
T Cell Subset ◽  
Oligoclonal Expansion

Abstract Abstract 1337 Erythroid hypoplasia or aplasia is a hematological condition observed in including idiopathic pure red cell aplasia (PRCA), thymoma-associated PRCA and aplastic anemia. Myelodysplastic syndrome (MDS) with erythroid hypoplasia/aplasia in bone marrow is a rare type of MDS that was not included in existing classifications of MDS. Patients with erythroid hypoplasia/aplasia have common characteristics; transfusion dependencies, immunologic abnormalities and successful immunosuppressive therapies with cyclosporin A (CsA). Thus, we may regard erythroid hypoplasia/aplasia as one of hematological disease entities. However, pathogenic mechanisms of erythroid hypoplasia/aplasia have not been fully elucidated, although T-lymphocyte-mediated inhibition of erythropoiesis is suspected to be the most possible mechanism of the pathogenesis. Recently, we reported that oligoclonal expansion of CD8+/perforin+ T cells was observed in patients with thymoma-associated PRCA and the oligoclonality was exclusively detected in CD8+ T cells, but not CD4+ T cells. To clarify the pathogenetic role of the T-cells, we analyzed the T-cell subsets and therapeutic responses in patients with erythroid hypoplasia/aplasia in bone marrow. Among 253 patients with MDS diagnosed at Hiroshima University Hospital between 2000 and June 2011, 12 patients (4.7%) showed erythroid hypoplasia/aplasia. A total of 22 patients with erythroid hypoplasia/aplasia, including 8 MDS with erythroid hypoplasia/aplasia, 3 idiopathic PRCA, 3 thymoma-associated PRCA and 8 aplastic anemia, were enrolled in this study. All patients were treated with CsA and improvement in anemia in this study followed the International Working Group (IWG) 2006 criteria. For T-cell subset analysis, mononuclear cells (MNCs) were purified from bone marrow (BM) or peripheral blood (PB) of the patients. MNCs were stained with fluorescent (FITC, PE, PerCP or APC)-conjugated antibodies for CD8, perforin, CCR7, CD62L, CD27, CD28 and CD45RO, CD45RA and were subjected to flow cytometric analysis. As controls, 30 patients with MDS without erythroid hypoplasia/aplasia and 30 patients without BM abnormalities were also analyzed. Among 22 patients with erythroid hypoplasia/aplasia, 10 patients (4 MDS with erythroid hypoplasia/aplasia, 1 idiopathic PRCA, 3 thymoma-associated PRCA and 2 aplastic anemia) responded to CsA therapy within 2 to 8 weeks. The median blood hemoglobin concentration increased from 6.5 g/dL at the baseline to 9.3 g/dL with treatment, with a median increase of hemoglobin of 2.8 g/dL from the baseline. We attempted to compare the T-cell subsets between CsA-responders and non-responders. All of 3 thymoma-associated PRCA showed good response to CsA therapy, suggesting that the oligoclonal expansion of a CD8+/perforin+ T-cell subset may be associated with the responses to immunosuppressive therapy. Thus, we focused on a T-cell subpopulation expressing CD8+/perforin+. Intriguingly, the CD8+/perforin+ T cells were significantly increased in the CsA-responders (44.3 ± 9.6%, n=10) compared to the non-responders (19.0 ± 9.3%, n=12, P<0.0001), normal BM controls (16.9 ± 7.0%, n=30) and MDS without erythroid hypoplasia/aplasia (15.1 ± 7.0%, n=30). Among the CD8+/perforin+ T cells, CD27+/CD62L+/−/CCR7low/CD28low/CD45RA++/CD45RO+ population was prominent, which is consistent with an effector memory T (TEM) cell subset described by Decrion et al. Our study reveals that CD8+/perforin+ T cell subset is a large population in the patients with CsA-responsive erythroid hypoplasia/aplasia. It is suggested that CD8+/perforin+ T cell subset may have functions to reduce erythroid progenitors via immunological mechanisms. The mechanisms may be easily suppressed by immunosuppressive therapies. In conclusion, expansion of CD8+/perforin+ T cell subset predicts response to cyclosporin A therapy in patients with erythroid hypoplasia/aplasia. The disease entity of “erythroid hypoplasia/aplasia in bone marrow with expansion of CD8+/perforin+ T cell subset”, including MDS, PRCA with or without thymoma and aplastic anemia, may have common pathogenetic mechanisms. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Tumoral PD-1hiCD8+ T cells are partially exhausted and predict favorable outcome in triple-negative breast cancer

2020 ◽  
Vol 134 (7) ◽  
pp. 711-726
Author(s):  
Liang Guo ◽  
Chunmei Cao ◽  
Shyamal Goswami ◽  
Xiaoyan Huang ◽  
Linxiaoxi Ma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Triple Negative ◽  
Tissue Microarrays ◽  
T Cell Subsets ◽  
Cell Subpopulation ◽  
Molecular Features

Abstract Tumor-infiltrating PD-1hi dysfunctional CD8+ T cells have been identified in several tumors but largely unexplored in breast cancer (BC). Here we aimed to extensively explore PD-1hiCD8+ T cells in BC, focusing on the triple-negative BC (TNBC) subtype. Flow cytometry was used to study the phenotypes and functions of CD8+ T-cell subsets in peripheral blood and surgical specimens from treatment-naive BC patients. RNA-seq expression data generated to dissect the molecular features of tumoral PD-1neg, PD-1lo and PD-1hi CD8+ T cells. Further, the associations between tumoral PD-1hi CD8+ T cells and the clinicopathological features of 503 BC patients were explored. Finally, multiplexed immunohistochemistry (mIHC) was performed to evaluate in situ PD-1hiCD8+ T cells on the tissue microarrays (TMAs, n=328) for prognostic assessment and stratification of TNBC patients. PD-1hiCD8+ T cells found readily detectable in tumor tissues but rarely in peripheral blood. These cells shared the phenotypic and molecular features with exhausted and tissue-resident memory T cells (TRM) with a skewed TCR repertoire involvement. Interestingly, PD-1hiCD8+ T cells are in the state of exhaustion characterized by higher T-BET and reduced EOMES expression. PD-1hiCD8+ T cells found preferentially enriched within solid tumors, but predominant stromal infiltration of PD-1hiCD8+ T subset was associated with improved survival in TNBC patients. Taken together, tumoral PD-1hiCD8+ T-cell subpopulation in BC is partially exhausted, and their abundance signifies ‘hot’ immune status with favorable outcomes. Reinvigorating this population may provide further therapeutic opportunities in TNBC patients.

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