A Variety of T-Cell Subsets Contribute to CD4+ T-Cell Infiltration in Diffuse Large B-Cell Lymphoma and Both Total CD4+ and CD4+FoxP3+ T-Cell Numbers Predict Clinical Outcome,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3684-3684
Author(s):  
Matthew J Ahearne ◽  
Kaljit S Bhuller ◽  
Roger Hew ◽  
Giovanna Roncador ◽  
Martin J.S. Dyer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Outcome ◽  
Cd4 T Cells ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Cell Infiltration ◽  
Good Clinical Outcome ◽  
Logrank Test ◽  
Tfh Cells

Abstract Abstract 3684 CD4+ T-cells can be distinguished into subsets on the basis of surface marker expression and growth factor production. Follicular helper T-cells (Tfh cells) are characterized by the co-expression of surface markers (CD4, ICOS, PD1 and CXCR5) and nuclear BCL6. Normal germinal centre formation requires Tfh cells but is repressed by another CD4+ T-cell subset, Tregs, (demonstrating CD4 and CD25 expression with nuclear FoxP3). The numbers and architecture of infiltrating T-cells predict clinical outcome in follicular lymphoma but although T-cells are a component of diffuse large B cell lymphoma (DLBCL), the relative numbers of CD4+ T-cells and their Tfh and Treg subsets or their association with clinical outcome is not known. We used immunohistochemistry to investigate infiltration by total CD4+, Treg and Tfh cells in cases (n=23) from one centre. The male:female was 1.3:1.0, the age range was 30 to 78 years (median 65 years) and the anticipated association between overall survival and LDH (logrank test, P=0.02) was observed. Patients were treated with R-CHOP with a 21-day cycle. Histological sections were stained with anti-CD4, anti-PD1 and anti-FoxP3 antibodies. For each antibody the area of staining was measured using ImageJ software from 10 high power fields from the same area of each histological section. Tfh cells were identified by strong surface expression of PD1 and Tregs by nuclear expression of FoxP3. CD4+ T-cell infiltration varied by ∼50-fold, and could be diffuse or focal. In 13 cases (57%) the majority of CD4+ T-cells were neither FoxP3+ nor PD1+. Total CD4+ T-cell numbers were positively correlated with FoxP3 (P=0.04) (Figure 1) and with PD1 (P=0.009) (Figure 2) expressing cells suggesting that these subsets were expanded as part of a reaction to the lymphoma capable of stimulating several CD4+ T-cell subsets. High CD4+ (Figure 3) and PD1+ staining predicted good clinical outcome (logrank test, P=0.08) with median survival not being reached at 5 years, but the amount of FoxP3+ staining appeared to be a superior prognostic marker (logrank test, P=0.0069) (Figure 4). There was no association between the cell of origin classification of DLBCL (GCB or ABC) as defined immunohistochemically, and CD4, FoxP3 or PD1 expression. In summary, we have shown that numbers of infiltrating CD4+ T-cells vary between cases of DLBCL and comprises several T-cell subsets including Treg and Tfh cells. No consensus has been reached on the clinical significance of FoxP3+ cell infiltration in DLBCL. Whilst some workers have shown FoxP3 to be associated with a good clinical outcome (Tzankov A., et al. 2008; Lee N., et al. 2008), others have not found a relationship to prognosis (Hasselblom S. et al., 2007). Our data shows that the FoxP3+ Treg cell subset is associated with good clinical outcome but surprisingly we found that both increased total CD4+ T-cells and PD1+ Tfh cells also carry a good prognosis. Disclosures: Wagner: Roche: Honoraria.

Both Stat5a and Stat5b are required for antigen-induced eosinophil and T-cell recruitment into the tissue

Blood ◽  
2000 ◽  
Vol 95 (4) ◽  
pp. 1370-1377 ◽  
Author(s):  
Shin-ichiro Kagami ◽  
Hiroshi Nakajima ◽  
Kotaro Kumano ◽  
Kotaro Suzuki ◽  
Akira Suto ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Specific Ige ◽  
Cd4 T Cell ◽  
Cell Infiltration ◽  
Cell Recruitment ◽  
Eosinophil Recruitment ◽  
Airway Eosinophilia ◽  
T Cell Infiltration

Antigen-induced eosinophil recruitment into the airways of sensitized mice is mediated by CD4+ T cells and their cytokines, especially IL-5. In this study, we found that the antigen-induced airway eosinophilia was diminished in Stat5a-deficient (Stat5a−/−) mice and Stat5b-deficient (Stat5b−/−) mice. We also found that antigen-induced CD4+ T-cell infiltration and IL-5 production in the airways were diminished in Stat5a−/− mice and Stat5b−/− mice. Moreover, antigen-induced proliferation of splenocytes was diminished in Stat5a−/− mice and Stat5b−/− mice, suggesting that the generation of antigen-primed T cells may be compromised in Stat5a−/−mice and Stat5b−/− mice and this defect may account for the diminished antigen-induced T-cell infiltration into the airways. Interestingly, IL-4 and IL-5 production from anti-CD3–stimulated splenocytes was diminished in Stat5a−/− mice and Stat5b−/− mice. However, antigen-specific IgE and IgG1 production was diminished in Stat5a−/− mice but not in Stat5b−/− mice, whereas antigen-specific IgG2a production was increased in Stat5a−/− mice, suggesting the enhanced Th1 responses in Stat5a−/− mice. Finally, we found that eosinophilopoiesis induced by the administration of recombinant IL-5 was also diminished in Stat5a−/− mice and Stat5b−/− mice. Together, these results indicate that both Stat5a and Stat5b are essential for induction of antigen-induced eosinophil recruitment into the airways and that the defects in antigen-induced eosinophil recruitment in Stat5a−/− mice and Stat5b−/− mice result from both impaired IL-5 production in the airways and diminished IL-5 responsiveness of eosinophils.

scholarly journals Cd4+ T Cell Subsets during Virus Infection

2000 ◽  
Vol 191 (12) ◽  
pp. 2159-2170 ◽  
Author(s):  
Kevin J. Maloy ◽  
Christoph Burkhart ◽  
Tobias M. Junt ◽  
Bernhard Odermatt ◽  
Annette Oxenius ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Cd4 T Cells ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Delayed Type Hypersensitivity ◽  
Protective Capacity ◽  
Peripheral Tissues

To analyze the antiviral protective capacities of CD4+ T helper (Th) cell subsets, we used transgenic T cells expressing an I-Ab–restricted T cell receptor specific for an epitope of vesicular stomatitis virus glycoprotein (VSV-G). After polarization into Th1 or Th2 effectors and adoptive transfer into T cell–deficient recipients, protective capacities were assessed after infection with different types of viruses expressing the VSV-G. Both Th1 and Th2 CD4+ T cells could transfer protection against systemic VSV infection, by stimulating the production of neutralizing immunoglobulin G antibodies. However, only Th1 CD4+ T cells were able to mediate protection against infection with recombinant vaccinia virus expressing the VSV-G (Vacc-IND-G). Similarly, only Th1 CD4+ T cells were able to rapidly eradicate Vacc-IND-G from peripheral organs, to mediate delayed-type hypersensitivity responses against VSV-G and to protect against lethal intranasal infection with VSV. Protective capacity correlated with the ability of Th1 CD4+ T cells to rapidly migrate to peripheral inflammatory sites in vivo and to respond to inflammatory chemokines that were induced after virus infection of peripheral tissues. Therefore, the antiviral protective capacity of a given CD4+ T cell is governed by the effector cytokines it produces and by its migratory capability.

scholarly journals CD4+ T cell subsets present stable relationships in their T cell receptor repertoires

2020 ◽  
Author(s):  
Shiyu Wang ◽  
Longlong Wang ◽  
Ya Liu
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Antigen Specificity ◽  
Sequence Composition

AbstractCD4+ T cells are key components of adaptive immunity. The cell differentiation equips CD4+ T cells with new functions. However, the effect of cell differentiation on T cell receptor (TCR) repertoire is not investigated. Here, we examined the features of TCR beta (TCRB) repertoire of the top clones within naïve, memory and regular T cell (Treg) subsets: repertoire structure, gene usage, length distribution and sequence composition. First, we found that memory subsets and Treg would be discriminated from naïve by the features of TCRB repertoire. Second, we found that the correlations between the features of memory subsets and naïve were positively related to differentiation levels of memory subsets. Third, we found that public clones presented a reduced proportion and a skewed sequence composition in differentiated subsets. Furthermore, we found that public clones led naïve to recognize a broader spectrum of antigens than other subsets. Our findings suggest that TCRB repertoire of CD4+ T cell subsets is skewed in a differentiation-depended manner. Our findings show that the variations of public clones contribute to these changes. Our findings indicate that the reduce of public clones in differentiation trim the antigen specificity of CD4+ T cells. The study unveils the physiological effect of memory formation and facilitates the selection of proper CD4+ subset for cellular therapy.

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 Tuberculosis Antigen-Specific T-Cell Responses During the First 6 Months of Antiretroviral Treatment

2019 ◽  
Vol 221 (1) ◽  
pp. 162-167 ◽  
Author(s):  
Catherine Riou ◽  
Nishtha Jhilmeet ◽  
Molebogeng X Rangaka ◽  
Robert J Wilkinson ◽  
Katalin A Wilkinson
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Antiretroviral Treatment ◽  
Cell Activation ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Immune Memory ◽  
Tuberculosis Antigen

Abstract The reconstitution of Mycobacterium tuberculosis antigen-specific CD4 T cells in a cohort of HIV-infected persons starting antiretroviral treatment (ART) in a high tuberculosis endemic area is described. Restoration of the antigen-specific CD4 T-cell subsets mirrored the overall CD4 T-cell compartment. Activation (assessed by HLA-DR expression) decreased during ART but remained elevated compared to HIV-uninfected persons. Despite known M. tuberculosis sensitization determined by interferon-γ release assay, 12/23 participants had no M. tuberculosis-specific CD4 T cells detectable by flow cytometry, combined with overall elevated T-cell activation and memory differentiation, suggesting heightened turnover. Our data suggest early ART initiation to maintain polyfunctional immune memory responses.

scholarly journals Regulatory CD4 T cells inhibit HIV-1 expression of other CD4 T cell subsets via interactions with cell surface regulatory proteins

Virology ◽  
2018 ◽  
Vol 516 ◽  
pp. 21-29 ◽  
Author(s):  
Mingce Zhang ◽  
Tanya O. Robinson ◽  
Alexandra Duverger ◽  
Olaf Kutsch ◽  
Sonya L. Heath ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Cd4 T Cells ◽  
Regulatory Proteins ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Hiv 1

scholarly journals Responsiveness of HIV-specific CD4 T cells to PD-1 blockade

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 965-974 ◽  
Author(s):  
Filippos Porichis ◽  
Douglas S. Kwon ◽  
Jennifer Zupkosky ◽  
Daniel P. Tighe ◽  
Ashley McMullen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cytokine Secretion ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Disease Stage ◽  
T Helper ◽  
The Impact

Abstract Defining the T helper functions impaired by programmed death–1 (PD-1) is crucial for understanding its role in defective HIV control and determining the therapeutic potential of targeting this inhibitory pathway. We describe here the relationships among disease stage, levels of PD-1 expression, and reversibility of CD4 T-cell impairment. PD-L1 blockade in vitro enhanced HIV-specific production of Th0 (IL-2), Th1 (IFN-γ), Th2 (IL-13), and TFH (IL-21) cytokines by CD4 T cells. PD-L1 blockade caused an early increase in cytokine transcription and translation that preceded cell proliferation. Although the impact of PD-L1 blockade on cytokine expression and, to a lesser extent, cell proliferation was associated with markers of disease progression, restoration of cytokine secretion was also observed in most subjects with undetectable viremia. PD-L1 blockade restored cytokine secretion in both PD-1intermediate and PD-1high sorted CD4 T-cell subsets. Compared with PD-1high HIV-specific CD8 T cells, PD-1high HIV-specific CD4 T cells showed lower expression of the inhibitory molecules CD160 and 2B4, demonstrating marked differences in expression of inhibitory receptors between T-cell subsets. These data show that PD-1 impairs HIV-specific T helper responses both by limiting expansion of these cells and by inhibiting effector functions of multiple differentiated CD4 T-cell subsets.

scholarly journals Aging is accompanied by a decrease in the number of naive Tregs

2021 ◽  
Vol 28 (Supplement_1) ◽  
Author(s):  
A Filatova ◽  
A Potekhina ◽  
N Radyukhina ◽  
N Ruleva ◽  
T Arefieva
Keyword(s):  
T Cells ◽  
T Cell ◽  
Negative Correlation ◽  
Cd4 T Cells ◽  
Carotid Atherosclerosis ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Absolute Content ◽  
Group Iii ◽  
The Absolute

Abstract Funding Acknowledgements Type of funding sources: None. Background. Age-related changes in the immune system are an important factor contributing to the maintenance of chronic inflammatory status. There are undoubted data on the decrease of the number of T-lymphocytes with age caused by thymus involution, but there are currently no unambiguous data on changes of minor T-cell subpopulations, in particular, regulatory T-cells (Treg). The aim of this study was to analyze the content of effector and regulatory CD4+ T cell subsets in patients with coronary and/or carotid atherosclerosis depending on age. Methods. 111 patients (men, median age 63 (55;69)) with coronary and/or carotid atherosclerosis, without smoking anamnesis, were enrolled.  Mononuclear leuocytes were isolated from blood by gradient centrifugation, and CD4 + CD25high and CD4 + Foxp3+ Treg, CD4 + IL17+ T-helpers (Th) 17 and CD4 + INFγ Th1 were evaluated by direct immunofluorescence and flow cytometry. For intracellular cytokine detection cells were pre-activated in vitro in the presence of PMA/ionomycin/brefeldin A. In 74 patients cells were additionally stained with CD39, CD278, CD45RA Mabs to reveal naïve and primed T-cells. Results. According to age the patients formed three groups: I – <55 y.o. (n = 23), II – 55-64 y.o. (n = 42), III - ≥65 y.o. (n = 46). All patients were taking statins at baseline. The groups were comparable in traditional risk factors of CVD (BMI, arterial hypertension, diabetes mellitus, previous myocardial infarction anamnesis). The absolute content of CD4+ T cells was lower in group III (646.3 (516.0;806.4)) compared to groups I (903.0 (585.6;1113.8), p = 0.03) and II (745.4 (502.2;924.0), p = 0.06). The absolute content of CD4 + CD25high Treg was lower in group III (24.2 (18.4;35.2)) compared to groups I (35.0 (28.7;54.4), p = 0.01) and II (31.0 (21.1;43.6), p = 0.03). There were no differences in Th1, Th17, CD39 + CD45RA- and CD278+ Treg content between groups. A negative correlation was found between age and the content of CD4+ T cells (r= -0.28), CD4 + CD25high Treg (r= -0.27), p < 0.05. A negative correlation was found between age and CD4 + CD25highCD45RA+ Treg (r= -0.24) and CD4 + CD45RA+ T cells (r= -0.36), CD4 + CD45RA+/CD4 + CD45RA- T-cells ratio (r= -0.24), p < 0.05. Conclusion. Here we demonstrate an age-dependent decrease of total CD4+ T cell population and Treg subset in patients with atherosclerosis. The changes observed were primary due to the deficiency of CD45RA+ naïve T cells. The effector cell Th1 and Th17 quantities were at the same levels. Future research will show whether the identified immunological patterns can contribute to the progression of atherosclerosis and other chronic inflammatory diseases.

scholarly journals Opposing effects of T cell receptor signal strength on CD4 T cells responding to acute versus chronic viral infection

2020 ◽  
Author(s):  
Marco Künzli ◽  
Peter Reuther ◽  
Daniel D. Pinschewer ◽  
Carolyn G. King
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cell Fate ◽  
Cd4 T Cells ◽  
Chronic Infection ◽  
Signal Strength ◽  
Cd4 T Cell ◽  
Chronic Viral Infection ◽  
Tfh Cells

AbstractA hallmark of the adaptive immune response is the ability of CD4 T cells to differentiate into a variety of pathogen appropriate and specialized effector subsets. A long-standing question in CD4 T cell biology is whether the strength of TCR signals can instruct one Th cell fate over another. The contribution of TCR signal strength to the development of Th1 and T follicular helper (Tfh) cells has been particularly difficult to resolve, with conflicting results reported in a variety of models. Although cumulative TCR signal strength can be modulated by the infection specific environment, whether or not TCR signal strength plays a dominant role in Th1 versus Tfh cell fate decisions across distinct infectious contexts is not known. Here we characterized the differentiation of CD4 TCR transgenic T cells responding to a panel of recombinant wild type or altered peptide ligand lymphocytic choriomeningitis viruses (LCMV) derived from acute and chronic parental strains. We found that while TCR signal strength positively regulates T cell expansion in both infection settings, it exerts opposite and hierarchical effects on the balance of Th1 and Tfh cells generated in response to acute versus persistent infection. The observation that weakly activated T cells, which comprise up to fifty percent of an endogenous CD4 T cell response, support the development of Th1 effectors highlights the possibility that they may resist functional inactivation during chronic infection. We anticipate that the panel of variant ligands and recombinant viruses described herein will be a valuable tool for immunologists investigating a wide range of CD4 T cell responses.Graphical abstractHighlightsIdentification of a wide panel of altered peptide ligands for the LCMV-derived GP61 peptideGeneration of LCMV variant strains to examine the impact of TCR signal strength on CD4 T cells responding during acute and chronic viral infectionThe relationship between TCR signal strength and Th1 differentiation shifts according to the infection context: TCR signal strength correlates positively with Th1 generation during acute infection but negatively during chronic infection.

scholarly journals Intestinal CD4 Depletion in HIV / SIV Infection

2019 ◽  
Vol 15 (1) ◽  
pp. 76-91
Author(s):  
Ronald S. Veazey
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Hiv Infection ◽  
Viral Replication ◽  
Cd4 T Cells ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Target Cells ◽  
Mucosal Integrity

Among the most significant findings in the pathogenesis of HIV infection was the discovery that almost total depletion of intestinal CD4+ T cells occurs rapidly after SIV or HIV infection, regardless of the route of exposure, and long before CD4+ T cell losses occur in blood or lymph nodes. Since these seminal discoveries, we have learned much about mucosal and systemic CD4+ T cells, and found several key differences between the circulating and intestinal CD4+ T cell subsets, both in phenotype, relative proportions, and functional capabilities. Further, specific subsets of CD4+ T cells are selectively targeted and eliminated first, especially cells critically important for initiating primary immune responses, and for maintenance of mucosal integrity (Th1, Th17, and Th22 cells). This simultaneously results in loss of innate immune responses, and loss of mucosal integrity, resulting in mucosal, and systemic immune activation that drives proliferation and activation of new target cells throughout the course of infection. The propensity for the SIV/HIV to infect and efficiently replicate in specific cells also permits viral persistence, as the mucosal and systemic activation that ensues continues to damage mucosal barriers, resulting in continued influx of target cells to maintain viral replication. Finally, infection and elimination of recently activated and proliferating CD4+ T cells, and infection and dysregulation of Tfh and other key CD4+ T cell results in hyperactive, yet non-protective immune responses that support active viral replication and evolution, and thus persistence in host tissue reservoirs, all of which continue to challenge our efforts to design effective vaccine or cure strategies.

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