scholarly journals Distinct Subsets of CD1d-restricted T Cells Recognize Self-antigens Loaded in Different Cellular Compartments

1999 ◽  
Vol 189 (1) ◽  
pp. 103-110 ◽  
Author(s):  
Ya-Hui Chiu ◽  
Jayanthi Jayawardena ◽  
Angela Weiss ◽  
Daniel Lee ◽  
Se-Ho Park ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Cd4 T Cells ◽  
Cell Subset ◽  
Gene Families ◽  
T Cell Subsets ◽  
Ifn Γ ◽  
Cellular Compartments ◽  
Self Antigens

Although recent studies have indicated that the major histocompatibility complex–like, β2-microglobulin–associated CD1 molecules might function to present a novel chemical class of antigens, lipids and glycolipids, to α/β T cells, little is known about the T cell subsets that interact with CD1. A subset of CD1d-autoreactive, natural killer (NK)1.1 receptor–expressing α/β T cells has recently been identified. These cells, which include both CD4−CD8− and CD4+ T cells, preferentially use an invariant Vα14-Jα281 T cell receptor (TCR) α chain paired with a Vβ8 TCR β chain in mice, or the homologous Vα24-JαQ/Vβ11 in humans. This cell subset can explosively release key cytokines such as interleukin (IL)-4 and interferon (IFN)-γ upon TCR engagement and may regulate a variety of infectious and autoimmune conditions. Here, we report the existence of a second subset of CD1d-restricted CD4+ T cells that do not express the NK1.1 receptor or the Vα14 TCR. Like the Vα14+ NK1.1+ T cells, these T cells exhibit a high frequency of autoreactivity to CD1d, use a restricted albeit distinct set of TCR gene families, and contribute to the early burst of IL-4 and IFN-γ induced by intravenous injection of anti-CD3. However, the Vα14+ NK1.1+ and Vα14− NK1.1− T cells differ markedly in their requirements for self-antigen presentation. Antigen presentation to the Vα14+ NK1.1+ cells requires endosomal targeting of CD1d through a tail-encoded tyrosine-based motif, whereas antigen presentation to the Vα14− NK1.1− cells does not. These experiments suggest the existence of two phenotypically different subsets of CD1d-restricted T cells that survey self-antigens loaded in distinct cellular compartments.

scholarly journals CRTAM determines the CD4+ cytotoxic T lymphocyte lineage

2015 ◽  
Vol 213 (1) ◽  
pp. 123-138 ◽  
Author(s):  
Arata Takeuchi ◽  
Mohamed El Sherif Gadelhaq Badr ◽  
Kosuke Miyauchi ◽  
Chitose Ishihara ◽  
Reiko Onishi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytotoxic Activity ◽  
Cd4 T Cells ◽  
Intracellular Signaling ◽  
Ectopic Expression ◽  
T Cell Subsets ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Ifn Γ

Naive T cells differentiate into various effector T cells, including CD4+ helper T cell subsets and CD8+ cytotoxic T cells (CTL). Although cytotoxic CD4+ T cells (CD4+CTL) also develop from naive T cells, the mechanism of development is elusive. We found that a small fraction of CD4+ T cells that express class I–restricted T cell–associated molecule (CRTAM) upon activation possesses the characteristics of both CD4+ and CD8+ T cells. CRTAM+ CD4+ T cells secrete IFN-γ, express CTL-related genes, such as eomesodermin (Eomes), Granzyme B, and perforin, after cultivation, and exhibit cytotoxic function, suggesting that CRTAM+ T cells are the precursor of CD4+CTL. Indeed, ectopic expression of CRTAM in T cells induced the production of IFN-γ, expression of CTL-related genes, and cytotoxic activity. The induction of CD4+CTL and IFN-γ production requires CRTAM-mediated intracellular signaling. CRTAM+ T cells traffic to mucosal tissues and inflammatory sites and developed into CD4+CTL, which are involved in mediating protection against infection as well as inducing inflammatory response, depending on the circumstances, through IFN-γ secretion and cytotoxic activity. These results reveal that CRTAM is critical to instruct the differentiation of CD4+CTL through the induction of Eomes and CTL-related gene.

scholarly journals Protein Energy Malnutrition during Vaccination Has Limited Influence on Vaccine Efficacy but Abolishes Immunity if Administered during Mycobacterium tuberculosis Infection

2015 ◽  
Vol 83 (5) ◽  
pp. 2118-2126 ◽  
Author(s):  
Truc Hoang ◽  
Else Marie Agger ◽  
Joseph P. Cassidy ◽  
Jan P. Christensen ◽  
Peter Andersen
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cd4 T Cells ◽  
Protein Energy Malnutrition ◽  
T Cell Subsets ◽  
Content Type ◽  
Protein Energy ◽  
Tnf Α ◽  
Ifn Γ

Protein energy malnutrition (PEM) increases susceptibility to infectious diseases, including tuberculosis (TB), but it is not clear how PEM influences vaccine-promoted immunity to TB. We demonstrate that PEM during low-level steady-state TB infection in a mouse model results in rapid relapse ofMycobacterium tuberculosis, as well as increased pathology, in bothMycobacterium bovisBCG-vaccinated and unvaccinated animals. PEM did not change the overall numbers of CD4 T cells in BCG-vaccinated animals but resulted in an almost complete loss of antigen-specific cytokine production. Furthermore, there was a change in cytokine expression characterized by a gradual loss of multifunctional antigen-specific CD4 T cells and an increased proportion of effector cells expressing gamma interferon and tumor necrosis factor alpha (IFN-γ+TNF-α+and IFN-γ+cells). PEM duringM. tuberculosisinfection completely blocked the protection afforded by the H56-CAF01 subunit vaccine, and this was associated with a very substantial loss of the interleukin-2-positive memory CD4 T cells promoted by this vaccine. Similarly, PEM during the vaccination phase markedly reduced the H56-CAF01 vaccine response, influencing all cytokine-producing CD4 T cell subsets, with the exception of CD4 T cells positive for TNF-α only. Importantly, this impairment was reversible and resupplementation of protein during infection rescued both the vaccine-promoted T cell response and the protective effect of the vaccine againstM. tuberculosisinfection.

scholarly journals Interplay between IL-10, IFN-γ, IL-17A and PD-1 Expressing EBNA1-Specific CD4+ and CD8+ T Cell Responses in the Etiologic Pathway to Endemic Burkitt Lymphoma

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5375
Author(s):  
Catherine S. Forconi ◽  
David H. Mulama ◽  
Priya Saikumar Lakshmi ◽  
Joslyn Foley ◽  
Juliana A. Otieno ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Burkitt Lymphoma ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Healthy Children ◽  
Ifn Γ

Children diagnosed with endemic Burkitt lymphoma (eBL) are deficient in interferon-γ (IFN-γ) responses to Epstein–Barr Nuclear Antigen1 (EBNA1), the viral protein that defines the latency I pattern in this B cell tumor. However, the contributions of immune-regulatory cytokines and phenotypes of the EBNA1-specific T cells have not been characterized for eBL. Using a bespoke flow cytometry assay we measured intracellular IFN-γ, IL-10, IL-17A expression and phenotyped CD4+ and CD8+ T cell effector memory subsets specific to EBNA1 for eBL patients compared to two groups of healthy children with divergent malaria exposures. In response to EBNA1 and a malaria antigen (PfSEA-1A), the three study groups exhibited strikingly different cytokine expression and T cell memory profiles. EBNA1-specific IFN-γ-producing CD4+ T cell response rates were lowest in eBL (40%) compared to children with high malaria (84%) and low malaria (66%) exposures (p < 0.0001 and p = 0.0004, respectively). However, eBL patients did not differ in CD8+ T cell response rates or the magnitude of IFN-γ expression. In contrast, eBL children were more likely to have EBNA1-specific CD4+ T cells expressing IL-10, and less likely to have polyfunctional IFN-γ+IL-10+ CD4+ T cells (p = 0.02). They were also more likely to have IFN-γ+IL-17A+, IFN-γ+ and IL-17A+ CD8+ T cell subsets compared to healthy children. Cytokine-producing T cell subsets were predominantly CD45RA+CCR7+ TNAIVE-LIKE cells, yet PD-1, a marker of persistent activation/exhaustion, was more highly expressed by the central memory (TCM) and effector memory (TEM) T cell subsets. In summary, our study suggests that IL-10 mediated immune regulation and depletion of IFN-γ+ EBNA1-specific CD4+ T cells are complementary mechanisms that contribute to impaired T cell cytotoxicity in eBL pathogenesis.

scholarly journals CD4+ T-Cell Plasticity in Non-Infectious Retinal Inflammatory Disease

2021 ◽  
Vol 22 (17) ◽  
pp. 9584
Author(s):  
Yi-Hsing Chen ◽  
Sue Lightman ◽  
Virginia L. Calder
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Cell Subset ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Dual Function ◽  
Interleukin 17 ◽  
Th1 Cells

Non-infectious uveitis (NIU) is a potentially sight-threatening disease. Effector CD4+ T cells, especially interferon-γ-(IFNγ) producing Th1 cells and interleukin-17-(IL-17) producing Th17 cells, are the major immunopathogenic cells, as demonstrated by adoptive transfer of disease in a model of experimental autoimmune uveitis (EAU). CD4+FoxP3+CD25+ regulatory T cells (Tregs) were known to suppress function of effector CD4+ T cells and contribute to resolution of disease. It has been recently reported that some CD4+ T-cell subsets demonstrate shared phenotypes with another CD4+ T-cell subset, offering the potential for dual function. For example, Th17/Th1 (co-expressing IFNγ and IL-17) cells and Th17/Treg (co-expressing IL-17 and FoxP3) cells have been identified in NIU and EAU. In this review, we have investigated the evidence as to whether these ‘plastic CD4+ T cells’ are functionally active in uveitis. We conclude that Th17/Th1 cells are generated locally, are resistant to the immunosuppressive effects of steroids, and contribute to early development of EAU. Th17/Treg cells produce IL-17, not IL-10, and act similar to Th17 cells. These cells were considered pathogenic in uveitis. Future studies are needed to better clarify their function, and in the future, these cell subsets may in need to be taken into consideration for designing treatment strategies for disease.

scholarly journals Gamma Interferon Responses of CD4 and CD8 T-Cell Subsets Are Quantitatively Different and Independent of Each Other during Pulmonary Mycobacterium bovis BCG Infection

2007 ◽  
Vol 75 (5) ◽  
pp. 2244-2252 ◽  
Author(s):  
Patricia Ngai ◽  
Sarah McCormick ◽  
Cherrie Small ◽  
Xizhong Zhang ◽  
Anna Zganiacz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Mycobacterial Infection ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Ifn Γ

ABSTRACT Gamma interferon (IFN-γ) is a key cytokine in host defense against intracellular mycobacterial infection. It has been believed that both CD4 and CD8 T cells are the primary sources of IFN-γ. However, the relative contributions of CD4 and CD8 T-cell subsets to IFN-γ production and the relationship between CD4 and CD8 T-cell activation have not been examined. By using a model of pulmonary mycobacterial infection and various immunodetection assays, we found that CD4 T cells mounted a much stronger IFN-γ response than CD8 T cells at various times after mycobacterial infection, and this pronounced IFN-γ production by CD4 T cells was attributed to both greater numbers of antigen-specific CD4 T cells and a greater IFN-γ secretion capacity of these cells. By using major histocompatibility complex class II-deficient or CD4-deficient mice, we found that the lack of CD4 T cells did not negatively affect primary or secondary CD8 T-cell IFN-γ responses. The CD8 T cells activated in the absence of CD4 T cells were capable of immune protection against secondary mycobacterial challenge. Our results suggest that, whereas both CD4 and CD8 T cells are capable of IFN-γ production, the former represent a much greater cellular source of IFN-γ. Moreover, during mycobacterial infection, CD8 T-cell IFN-γ responses and activation are independent of CD4 T-cell activation.

scholarly journals Functional biomarker signatures of circulating T-cells and its association with distinct clinical status of leprosy patients and their respective household contacts

2020 ◽  
Author(s):  
Pedro Henrique Ferreira Marçal ◽  
Rafael Silva Gama ◽  
Lorena Bruna de Oliveira Pereira ◽  
Olindo Assis Martins Filho ◽  
Roberta Olmo Pinheiro ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Clinical Status ◽  
T Cell Subsets ◽  
Diagnostic Tools ◽  
Household Contacts ◽  
Leprosy Patients ◽  
Ifn Γ

Abstract Background: Leprosy is a chronic infectious disease classified into two subgroups for therapeutic purposes: paucibacillary (PB) and multibacillary (MB), closely related to the host immune responses. In this context it is noteworthy looking for immunological biomarkers applicable as complementary diagnostic tools as well as a laboratorial strategy to detect subclinical leprosy in household contacts. Methods: The main goal of the present study was to characterize the global cytokine signatures of CD4 + and CD8 + T-cells from leprosy patients with distinct clinical forms and their respective household contacts (HHC) upon in vitro antigen-specific stimuli. Short-term culture of peripheral blood mononuclear cells was done. After incubation, cells were harvested and prepared for surface and intracytoplasmic cytokine staining Results: The cytokine signature analysis demonstrated that leprosy patients presented a polyfunctional profile of T-cells subsets, with increased frequency of IFN-γ + T-cell subsets along with IL-10 + and IL-4 + from CD4 + T-cells. Moreover, L(PB) displayed a polyfunctional profile characterized by enhanced percentage of IFN-γ + , IL-10 + and IL-4 + produced by most T-cell subsets, as compared to L(MB) that presented a more restricted cytokine functional profile mediated by IL-10 + and IL-4 + T-cells with minor contribution of IFN-γ produced by CD4 + T-cells. Noteworthy was that HHC(MB) exhibited enhanced frequency of IFN-γ + T-cells, contrasting with HHC(PB) that presented a cytokine profile limited to IL-10 and IL-4. Conclusions: Together, our findings provide additional immunological features associated with leprosy and household contacts. These data provide evidence that biomarkers of immune response can be useful complementary diagnostic/prognostic tools as well as insights that household contacts may present subclinical infection. Keywords: leprosy, Mycobacterium leprae , cytokines, household contacts

scholarly journals T-Cell Cytokine Response in Salmonella Typhimurium-Vaccinated versus Infected Pigs

Vaccines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 845
Author(s):  
Selma Schmidt ◽  
Heinrich Kreutzmann ◽  
Maria Stadler ◽  
Kerstin H. Mair ◽  
Melissa R. Stas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Salmonella Typhimurium ◽  
Cd4 T Cells ◽  
T Cell Subsets ◽  
Local Immunity ◽  
Effective Measure ◽  
Treatment Groups ◽  
Tnf Α ◽  
Ifn Γ

Vaccination with the live attenuated vaccine Salmoporc is an effective measure to control Salmonella Typhimurium (STM) in affected swine populations. However, the cellular immune response evoked by the Salmoporc vaccine including differences in vaccinated pigs versus non-vaccinated pigs upon STM infection have not been characterized yet. To investigate this, tissue-derived porcine lymphocytes from different treatment groups (vaccination-only, vaccination and infection, infection-only, untreated controls) were stimulated in vitro with heat-inactivated STM and abundances of IFN-γ, TNF-α and/or IL-17A-producing T-cell subsets were compared across organs and treatment groups. Overall, our results show the induction of a strong CD4+ T-cell response after STM infection, both locally and systemically. Low-level induction of STM-specific cytokine-producing CD4+ T cells, notably for the IFN-γ/TNF-α co-producing phenotype, was detected after vaccination-only. Numerous significant contrasts in cytokine-producing T-cell phenotypes were observed after infection in vaccinated and infected versus infected-only animals. These results suggest that vaccine-induced STM-specific cytokine-producing CD4+ T cells contribute to local immunity in the gut and may limit the spread of STM to lymph nodes and systemic organs. Hence, our study provides insights into the underlying immune mechanisms that account for the efficacy of the Salmoporc vaccine.

Dysfunctional Tregs with Absence of Cytokine-Secreting CD4+ T-Cell Subsets and Marked Expansion of Th1 Cells Is a Hallmark of Idiopathic Aplastic Anaemia (AA)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2233-2233
Author(s):  
Shahram Kordasti ◽  
Judith C. W. Marsh ◽  
Pilar Perez Abellan ◽  
Sufyan Alkhan ◽  
Janet Hayden ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Cd4 T Cells ◽  
Cytokine Secretion ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Th1 Cells ◽  
Healthy Controls ◽  
Ifn Γ

Abstract Abstract 2233 Introduction: Autoimmunity is an important contributor in the aetiology of AA. Although the expansion of oligoclonal CD8+ T-cells and their correlation with response to immunosuppressive therapy (IST) has been reported previously, the role of CD4+ in the pathogenesis is not elucidated. The focus of this study was to investigate the role of different CD4+ T-cell subsets, including regulatory T-cells (Tregs) and T helpers (Th1, Th2 and Th17) in the pathobiology of idiopathic AA. Patients and Methods: The percentage and absolute numbers of CD4+ and CD8+ T-cell subsets, NK & B cells and dendritic cells (DCs) in peripheral blood were assessed in 42 patients with idiopathic AA prior to any IST and 8 healthy age matched controls. T-cells were stimulated first and stained intracellularly for IFN-γ and TNF-a (Th1), IL-4 (Th2) and IL-17 (Th17). Serum levels of 30 cytokines were measured by 30 Plex bead analysis (Luminex). NK cells were defined as CD3– CD56+. B cells were defined as CD3-CD19+. CD3+ CD4+.T-cell subsets were defined as CD45RO–CD27+ naïve, CD45RO+ CD27+ CD62L+ central memory, CD45RO+ CD27+ CD62L– effector memory, CD45RO+CD27– effectors and CD45RO– CD27– terminal effectors. DCs were defined based on their BDCA 1,2, 3 & CD16 expression. CD4 Tregs were defined as CD3+CD4+ CD25high CD27+Foxp3+. Treg subsets were defined as (1) CD45RA+CD25lo resting Tregs, (2) CD45RA-CD25hi activated Tregs, and (3) cytokine-secreting CD45RA-CD25lo non-Tregs1. Treg function was evaluated by cytokine secretion of T effector cells (Te) with and without Tregs. IFN-γ secreting CD4+ T-cells (Th1) were enriched by magnetic beads followed by FACS sorting. The clonality of Th1 cells was evaluated based on the diversity of T-cell receptors by spectratyping as well as sequencing. Transcription factor expression was measured by qPCR. Results: There were no significant differences in the number or percentage of different CD8 T-cells compared to healthy controls. Surprisingly, despite a borderline decrease in the absolute number of naïve (p=0.19) and central memory (p=0.20) CD4+T-cells the number and percentage of Tregs were no different from healthy controls (1.36×107/L v 1.34×107/L, p=0.57). Although the ratio of Tregs to CD4+ T-effectors (Te) was higher than in healthy controls, the difference was not significant (0.49 v 0.12, p=0.86). The absolute numbers and percentages of Th1 cells and TNF-α + CD4+ T-cells were significantly higher in AA patients compared to healthy controls (4.2 × 107/L v 0.9 × 107/L & 2.44 × 108 v 1.26 × 108(p=0.001, p=0.004)). The diversity of T-cell receptor on Th1 cells was significantly lower compared to healthy age matched controls (on average 21 & 52 peaks). Amongst AA patients, the numbers of Th2, Th17, NK and B cells were not significantly different from healthy controls, whereas the absolute numbers of all DCs were reduced(p<0.01). The serum levels of proliferative cytokines, EGF (p=0.01), HGF (p=0.01), VEGF (p=0.01) and pro-inflammatory cytokines IL-13 (p=0.02), IL-8 (p<0.001) were significantly higher in AA patients. The percentage of cytokine secreting CD4+ CD25+ T-cells was markedly decreased in AA patients and the activated Treg subsets were predominantly of CD45RA+ phenotype, which was significantly different from healthy controls. Sorted Tregs from AA patients were unable to suppress cytokine secretion by Te cells in a 1:1 co-culture. However, IL-2, IFN-γ and TNF-α secretion of Te from AA patients was suppressible by allogeneic Tregs from healthy controls (on average 11 time suppression), whereas Tregs from AA patients were unable to suppress healthy Te cells. However, dysfunctional Tregs were not associated with abnormality of transcription factors, as judged by the levels of STAT1, 3, 4, 5 & 6, FoxP3 & T-bet of Tregs that were not significantly different from healthy age matched controls. Conclusion: Our data show that although FoxP3+ Tregs are normal in AA, a subset of these cells is markedly reduced and the activated Tregs aberrantly express CD45RA. Furthermore, unlike normal Tregs, the Tregs from AA patients do not suppress the inflammatory cytokine secretion by Te cells. The absence of DCs in the peripheral blood suggests their immigration to the inflammation site (e.g. bone marrow), which may play a role in the polarisation of T helpers toward a Th1 phenotype. Clonal expansion of Th1 cells may suggest potential antigen specificity that may lead to AA phenotype. 1. Miyara M, et al. Immunity. 2009. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Single cell sequencing reveals expanded cytotoxic CD4+ T cells and two states of peripheral helper T cells in synovial fluid of ACPA+ RA patients

2021 ◽  
Author(s):  
Alexandra Argyriou ◽  
Marc H Wadsworth ◽  
Adrian Lendvai ◽  
Stephen M Christensen ◽  
Aase Hensvold ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Synovial Fluid ◽  
Single Cell ◽  
Cd4 T Cells ◽  
Cell Subset ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
T Cell Subset ◽  
Single Cell Sequencing

Rheumatoid arthritis is an autoimmune disease affecting the synovial joints where different subsets of CD4+ T cells are suspected to play a pathogenic role. So far, our understanding of the contribution of cytotoxic CD4+ T cells is incomplete, particularly in the context of the recently described peripheral helper T-cell subset (TPH). Here, using single cell sequencing and multi-parameter flow cytometry, we show that cytotoxic CD4+ T cells are enriched in synovial fluid of anti-citrullinated peptides antibody (ACPA)-positive RA patients. We identify two distinct TPH states differentially characterized by the expression of CXCL13 and PRDM1, respectively. Our data reveal that the adhesion G-Protein Coupled Receptor 56 (GPR56), a marker of circulating cytotoxic cells, delineates the synovial TPH CD4+ T-cell subset. At the site of inflammation, GPR56+CD4+ T cells expressed the tissue-resident memory markers LAG-3, CXCR6 and CD69. Further, TCR clonality analysis revealed that most expanded clones in SF are contained within the cytotoxic and the CXCL13+ TPH CD4+ T-cell populations. Finally, the detection of common TCRs between the two TPH and cytotoxic CD4+ T-cell clusters suggest a shared differentiation. Our study provides comprehensive immunoprofiling of the heterogenous T-cell subsets at the site of inflammation in ACPA+ RA and suggests GPR56 as a therapeutic target to modulate TPH cells and cytotoxic CD4+ T cell function

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