scholarly journals Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines

Blood ◽  
2008 ◽  
Vol 112 (3) ◽  
pp. 610-618 ◽  
Author(s):  
Michael A. Morse ◽  
Amy C. Hobeika ◽  
Takuya Osada ◽  
Delila Serra ◽  
Donna Niedzwiecki ◽  
...  
Keyword(s):  
Single Dose ◽  
T Cell ◽  
Immune Responses ◽  
Treg Cell ◽  
Dose Group ◽  
Flow Cytometric Analysis ◽  
Treg Cells ◽  
T Cell Response ◽  
Cell Depletion ◽  
Denileukin Diftitox

Abstract CD4+CD25highFoxP3+ regulatory T (Treg) cells limit antigen-specific immune responses and are a cause of suppressed anticancer immunity. In preclinical and clinical studies, we assessed the immune consequences of FoxP3+ Treg-cell depletion in patients with advanced malignancies. We demonstrated that a CD25high targeting immunotoxin (denileukin diftitox) depleted FoxP3+ Treg cells, decreased Treg-cell function, and enhanced antigen-specific T-cell responses in vitro. We then attempted to enhance antitumor immune responses in patients with carcinoembryonic antigen (CEA)–expressing malignancies by Treg-cell depletion. In a pilot study (n = 15), denileukin diftitox, given as a single dose or repeated dosing, was followed by immunizations with dendritic cells modified with the fowlpox vector rF-CEA(6D)-TRICOM. By flow cytometric analysis, we report the first direct evidence that circulating CD4+CD25highFoxP3+ Treg cells are depleted after multiple doses of denileukin diftitox. Earlier induction of, and overall greater exposure to, the T-cell response to CEA was observed in the multiple-dose group, but not the single-dose group. These results indicate the potential for combining Treg-cell depletion with anticancer vaccines to enhance tumor antigen-specific immune responses and the need to explore dose and schedule of Treg depletion strategies in optimiz-ing vaccine efforts. This trial was registered at www.clinicaltrials.gov as no. NCT00128622.

scholarly journals IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3192-3201 ◽  
Author(s):  
Mary T. Litzinger ◽  
Romaine Fernando ◽  
Tyler J. Curiel ◽  
Douglas W. Grosenbach ◽  
Jeffrey Schlom ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Viral Vector ◽  
Interleukin 2 ◽  
Treg Cells ◽  
Denileukin Diftitox ◽  
Host Immune Responses ◽  
Cell Immunity ◽  
T Cell Immune Responses ◽  
Cellular Compartments

AbstractCD4+CD25+Foxp3+ regulatory T (Treg) cells have been implicated in the lack of effective antitumor immunity. Denileukin diftitox (DAB389IL-2), a fusion protein of interleukin 2 (IL-2) and diphtheria toxin, provides a means of targeting Treg cells. In this study, we examined (1) the effect of denileukin diftitox on the deletion of Treg cells in various lymphoid compartments and (2) the dose scheduling of denileukin diftitox in combination with a recombinant poxviral vaccine to enhance antigen-specific immune responses. Treg cells in spleen, peripheral blood, and bone marrow of normal C57BL/6 mice were variously reduced after a single intraperitoneal injection of denileukin diftitox; the reduction was evident within 24 hours and lasted approximately 10 days. Injection of denileukin diftitox 1 day before vaccination enhanced antigen-specific T-cell responses above levels induced by vaccination alone. These studies show for the first time in a murine model (1) the differential effects of denileukin diftitox on Treg cells in different cellular compartments, (2) the advantage of combining denileukin diftitox with a vaccine to enhance antigen-specific T-cell immune responses, (3) the lack of inhibition by denileukin diftitox of host immune responses directed against a live viral vector, and (4) the importance of dose scheduling of denileukin diftitox when used in combination with a vaccine.

scholarly journals Targeting of Cdc42 GTPase in regulatory T cells unleashes anti-tumor T cell immunity

2021 ◽  
Author(s):  
Khalid W Kalim ◽  
Jun-Qi Yang ◽  
Mark Wunderlich ◽  
Vishnu Modur ◽  
Phuong Nguyen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cell ◽  
Cell Function ◽  
Treg Cells ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Cell Plasticity ◽  
Effector T Cell ◽  
Cell Immunity

Regulatory T (Treg) cells play an important role in maintaining immune tolerance through inhibiting effector T cell function. In the tumor microenvironment, Treg cells are utilized by tumor cells to counteract effector T cell-mediated tumor killing. Targeting Treg cells may thus unleash the anti-tumor activity of effector T cells. While systemic depletion of Treg cells can cause excessive effector T cell responses and subsequent autoimmune diseases, controlled targeting of Treg cells may benefit cancer patients. Here we show that Treg cell-specific heterozygous deletion or pharmacological targeting of Cdc42 GTPase does not affect Treg cell numbers but induces Treg cell plasticity, leading to anti-tumor T cell immunity without detectable autoimmune reactions. Cdc42 targeting potentiates an immune checkpoint blocker anti-PD-1 antibody-mediated T cell response against mouse and human tumors. Mechanistically, Cdc42 targeting induces Treg cell plasticity and unleashes anti-tumor T cell immunity through carbonic anhydrase I-mediated pH changes. Thus, rational targeting of Cdc42 in Treg cells holds therapeutic promises in cancer immunotherapy.

Most human thymic and peripheral-blood CD4+CD25+ regulatory T cells express 2 T-cell receptors

Blood ◽  
2006 ◽  
Vol 108 (13) ◽  
pp. 4063-4070 ◽  
Author(s):  
Heli Tuovinen ◽  
Jukka T. Salminen ◽  
T. Petteri Arstila
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cell ◽  
Flow Cytometric Analysis ◽  
Cell Lineage ◽  
Cell Receptor ◽  
Treg Cells ◽  
Allelic Exclusion ◽  
Dual Specificity ◽  
Functional Consequences

Abstract Lack of allelic exclusion in the T-cell receptor (TCR) α locus gives rise to 2 different TCRs in 10% to 30% of all mature T cells, but the significance of such dual specificity remains controversial. Here we show that human CD4+CD25+ regulatory T (Treg) cells express 2 distinct Vα chains and thus 2 TCRs at least 3 times as often as other T cells. Extrapolating from flow cytometric analysis using Vα2-, Vα12-, and Vα24-specific monoclonal antibodies (mAbs), we estimated that between 50% and 99% of the CD25+ Treg cells were dual specific, as compared with about 20% of their CD25– counterparts. Moreover, both TCRs were equally capable of transmitting signals upon ligation. Cells with 2 TCRs also expressed more FOXP3, the Treg-cell lineage specification factor, than cells with a single TCR. Our findings suggest that expression of 2 TCRs favors differentiation to the Treg-cell lineage in humans and raise the question of the potential functional consequences of dual specificity.

scholarly journals Two doses of SARS-CoV-2 vaccination induce robust immune responses to emerging SARS-CoV-2 variants of concern

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Donal T. Skelly ◽  
Adam C. Harding ◽  
Javier Gilbert-Jaramillo ◽  
Michael L. Knight ◽  
Stephanie Longet ◽  
...  
Keyword(s):  
T Cells ◽  
Single Dose ◽  
T Cell ◽  
Immune Responses ◽  
Natural Infection ◽  
T Cell Response ◽  
High Potency ◽  
Cell Responses ◽  
Reference Isolate ◽  
High Magnitude

AbstractThe extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from natural infection in early 2020. We show that neutralization of the VOC compared to a reference isolate of the original circulating lineage, B, is reduced: more profoundly against B.1.351 than for B.1.1.7, and in responses to infection or a single dose of vaccine than to a second dose of vaccine. Importantly, high magnitude T cell responses are generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. Vaccination is required to generate high potency immune responses to protect against these and other emergent variants.

scholarly journals Decreased Treg Cell and TCR Expansion Are Involved in Long-Lasting Graves’ Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Ziyi Chen ◽  
Yufeng Liu ◽  
Shiqian Hu ◽  
Meng Zhang ◽  
Bingyin Shi ◽  
...  
Keyword(s):  
T Cell ◽  
Treg Cell ◽  
Flow Cytometric Analysis ◽  
Autoimmune Disorder ◽  
Cell Receptor ◽  
Treg Cells ◽  
Thyroid Stimulating Hormone ◽  
Graves Disease ◽  
Rna Seq ◽  
Flow Cytometric

Graves’ disease (GD) is a T cell-mediated organ-specific autoimmune disorder. GD patients who have taken anti-thyroid drugs (ATDs) for more than 5 years with positive anti-thyroid stimulating hormone receptor autoantibodies value were defined as persistent GD (pGD). To develop novel immunotherapies for pGD, we investigated the role of T cells in the long-lasting phase of GD. Clinical characteristics were compared between the pGD and newly diagnosed GD (nGD) (N = 20 respectively). Flow cytometric analysis was utilized to determine the proportions of Treg and Th17 cells (pGD, N = 12; nGD, N = 14). T cell receptor sequencing (TCR-seq) and RNA sequencing (RNA-seq) were also performed (pGD, N = 13; nGD, N = 20). Flow cytometric analysis identified lower proportions of Th17 and Treg cells in pGD than in nGD (P = 0.0306 and P = 0.0223). TCR-seq analysis revealed a lower diversity (P = 0.0025) in pGD. Specifically, marked clonal expansion, represented by an increased percentage of top V-J recombination, was observed in pGD patients. Interestingly, pGD patients showed more public T cell clonotypes than nGD patients (2,741 versus 966). Meanwhile, RNA-seq analysis revealed upregulation of the inflammation and chemotaxis pathways in pGD. Specifically, the expression of pro-inflammatory and chemotactic genes (IL1B, IL13, IL8, and CCL4) was increased in pGD, whereas Th17 and Treg cells associated genes (RORC, CARD9, STAT5A, and SATB1) decreased in pGD. Additionally, TCR diversity was negatively correlated with the expression of pro-inflammatory or chemotactic genes (FASLG, IL18R1, CCL24, and CCL14). These results indicated that Treg dysregulation and the expansion of pathogenic T cell clones might be involved in the long-lasting phase of GD via upregulating chemotaxis or inflammation response. To improve the treatment of pGD patients, ATDs combined therapies, especially those aimed at improving Treg cell frequencies or targeting specific expanded pathogenic TCR clones, are worth exploring in the future.

scholarly journals Foxp3+ CD4+ regulatory T cells control dendritic cells in inducing antigen-specific immunity to emerging SARS-CoV-2 antigens

2021 ◽  
Vol 17 (12) ◽  
pp. e1010085
Author(s):  
Ryuta Uraki ◽  
Masaki Imai ◽  
Mutsumi Ito ◽  
Hiroaki Shime ◽  
Mizuyu Odanaka ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Treg Cell ◽  
Treg Cells ◽  
Immunological Tolerance ◽  
Cell Depletion ◽  
Humoral And Cellular Immunity ◽  
Specific Immunity ◽  
Antigen Presenting

Regulatory T (Treg) cells, which constitute about 5–10% of CD4+T cells expressing Foxp3 transcription factor and CD25(IL-2 receptor α chain), are key regulators in controlling immunological self-tolerance and various immune responses. However, how Treg cells control antigen-specific immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. In this study, we examined the effect of transient breakdown of the immunological tolerance induced by Treg-cell depletion on adaptive immune responses against administered SARS-CoV-2 antigen, spike protein 1 (S1). Notably, without the use of adjuvants, transient Treg-cell depletion in mice induced anti-S1 antibodies that neutralized authentic SARS-CoV-2, follicular helper T cell formation and S1-binding germinal center B cell responses, but prevented the onset of developing autoimmune diseases. To further clarify the mechanisms, we investigated maturation of dendritic cells (DCs), which is essential to initiate antigen-specific immunity. We found that the transient Treg-cell depletion resulted in maturation of both migratory and resident DCs in draining lymph nodes that captured S1-antigen. Moreover, we observed S1-specific CD4+ T cells and CD8+ T cells with interferon-γ production. Thus, captured S1 was successfully presented by DCs, including cross-presentation to CD8+ T cells. These data indicate that transient Treg-cell depletion in the absence of adjuvants induces maturation of antigen-presenting DCs and succeeds in generating antigen-specific humoral and cellular immunity against emerging SARS-CoV-2 antigens. Finally, we showed that SARS-CoV-2 antigen-specific immune responses induced by transient Treg-cell depletion in the absence of adjuvants were compatible with those induced with an effective adjuvant, polyriboinosinic:polyribocytidyl acid (poly IC) and that the combination of transient Treg-cell depletion with poly IC induced potent responses. These findings highlight the capacity for manipulating Treg cells to induce protective adaptive immunity to SARS-CoV-2 with activating antigen-presenting DCs, which may improve the efficacy of ongoing vaccine therapies and help enhance responses to emerging SARS-CoV-2 variants.

scholarly journals Efficient IL-2R signaling differentially affects the stability, function, and composition of the regulatory T-cell pool

2021 ◽  
Author(s):  
Marc Permanyer ◽  
Berislav Bošnjak ◽  
Silke Glage ◽  
Michaela Friedrichsen ◽  
Stefan Floess ◽  
...  
Keyword(s):  
T Cell ◽  
Treg Cell ◽  
Cell Function ◽  
Interleukin 2 ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Receptor Expression ◽  
Spontaneous Mutant ◽  
Cell Pool ◽  
And Function

AbstractSignaling via interleukin-2 receptor (IL-2R) is a requisite for regulatory T (Treg) cell identity and function. However, it is not completely understood to what degree IL-2R signaling is required for Treg cell homeostasis, lineage stability and function in both resting and inflammatory conditions. Here, we characterized a spontaneous mutant mouse strain endowed with a hypomorphic Tyr129His variant of CD25, the α-chain of IL-2R, which resulted in diminished receptor expression and reduced IL-2R signaling. Under noninflammatory conditions, Cd25Y129H mice harbored substantially lower numbers of peripheral Treg cells with stable Foxp3 expression that prevented the development of spontaneous autoimmune disease. In contrast, Cd25Y129H Treg cells failed to efficiently induce immune suppression and lost lineage commitment in a T-cell transfer colitis model, indicating that unimpaired IL-2R signaling is critical for Treg cell function in inflammatory environments. Moreover, single-cell RNA sequencing of Treg cells revealed that impaired IL-2R signaling profoundly affected the balance of central and effector Treg cell subsets. Thus, partial loss of IL-2R signaling differentially interferes with the maintenance, heterogeneity, and suppressive function of the Treg cell pool.

scholarly journals Quantitative analysis of the CD8 + T–cell response to readily eliminated and persistent viruses

2000 ◽  
Vol 355 (1400) ◽  
pp. 1093-1101 ◽  
Author(s):  
P. C. Doherty ◽  
J. M. Riberdy ◽  
G. T. Belz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Influenza A ◽  
Flow Cytometric Analysis ◽  
T Cell Response ◽  
Basic Question ◽  
Cell Mediated Immunity ◽  
Specific Response ◽  
Turnover Rates

The recent development of techniques for the direct staining of peptide–specific CD8 + T cells has revolutionized the analysis of cell–mediated immunity (CMI) in virus infections. This approach has been used to quantify the acute and long–term consequences of infecting laboratory mice with the readily eliminated influenza A viruses (fluA) and a persistent γherpesvirus (γHV). It is now, for the first time, possible to work with real numbers in the analysis of CD8 + T CMI, and to define various characteristics of the responding lymphocytes both by direct flow cytometric analysis and by sorting for further in vitro manipulation. Relatively little has yet been done from the latter aspect, though we are rapidly accumulating a mass of numerical data. The acute, antigen–driven phases of the fluA and γHV–specific response look rather similar, but CD8 + T–cell numbers are maintained in the long term at a higher ‘set point’ in the persistent infection. Similarly, these ‘memory’ T cells continue to divide at a much greater rate in the γHV–infected mice. New insights have also been generated on the nature of the recall response following secondary challenge in both experimental systems, and the extent of protection conferred by large numbers of virus–specific CD8 + T cells has been determined. However, there are still many parameters that have received little attention, partly because they are difficult to measure. These include the rate of antigen–specific CD8 + T–cell loss, the extent of the lymphocyte ‘diaspora’ to other tissues, and the diversity of functional characteristics, turnover rates, clonal life spans and recirculation profiles. The basic question for immunologists remains how we reconcile the extraordinary plasticity of the immune system with the mechanisms that maintain a stable milieu interieur. This new capacity to quantify CD8 + T–cell responses in readily manipulated mouse models has obvious potential for illuminating homeostatic control, particularly if the experimental approaches to the problem are designed in the context of appropriate predictive models.

scholarly journals Immune Restoration Diseases Reflect Diverse Immunopathological Mechanisms

2009 ◽  
Vol 22 (4) ◽  
pp. 651-663 ◽  
Author(s):  
Patricia Price ◽  
David M. Murdoch ◽  
Upasna Agarwal ◽  
Sharon R. Lewin ◽  
Julian H. Elliott ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
De Novo ◽  
Granulomatous Inflammation ◽  
T Cell Response ◽  
Immune Restoration ◽  
Immunological Parameters ◽  
Varicella Zoster

SUMMARY Up to one in four patients infected with human immunodeficiency virus type 1 and given antiretroviral therapy (ART) experiences inflammatory or cellular proliferative disease associated with a preexisting opportunistic infection, which may be subclinical. These immune restoration diseases (IRD) appear to result from the restoration of immunocompetence. IRD associated with intracellular pathogens are characterized by cellular immune responses and/or granulomatous inflammation. Mycobacterial and cryptococcal IRD are attributed to a pathological overproduction of Th1 cytokines. Clinicopathological characteristics of IRD associated with viral infections suggest different pathogenic mechanisms. For example, IRD associated with varicella-zoster virus or JC polyomavirus infection correlate with a CD8 T-cell response in the central nervous system. Exacerbations or de novo presentations of hepatitis associated with hepatitis C virus (HCV) infection following ART may also reflect restoration of pathogen-specific immune responses as titers of HCV-reactive antibodies rise in parallel with liver enzymes and plasma markers of T-cell activation. Correlations between immunological parameters assessed in longitudinal sample sets and clinical presentations are required to illuminate the diverse immunological scenarios described collectively as IRD. Here we present salient clinical features and review progress toward understanding their pathogeneses.

scholarly journals Granzyme B is not required for regulatory T cell–mediated suppression of graft-versus-host disease

Blood ◽  
2010 ◽  
Vol 115 (9) ◽  
pp. 1669-1677 ◽  
Author(s):  
Sheng F. Cai ◽  
Xuefang Cao ◽  
Anjum Hassan ◽  
Todd A. Fehniger ◽  
Timothy J. Ley
Keyword(s):  
Immune Responses ◽  
Treg Cell ◽  
Graft Versus Host Disease ◽  
Granzyme B ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Treg Cells ◽  
Host Disease ◽  
Graft Versus Host

Abstract Regulatory T (Treg) cells can suppress a wide variety of immune responses, including antitumor and alloimmune responses. The mechanisms by which Treg cells mediate their suppressive effects depend on the context of their activation. We previously reported that granzyme B is important for Treg cell–mediated suppression of antitumor immune responses. We therefore hypothesized that granzyme B may likewise be important for suppression of graft-versus-host disease (GVHD). We found that allogeneic mismatch induces the expression of granzyme B in mixed lymphocyte reactions and in a model of graft-versus-host disease (GVHD). However, wild-type and granzyme B–deficient Treg cells were equally able to suppress effector T (Teff) cell proliferation driven by multiple stimuli, including allogeneicantigen-presenting cells. Surprisingly, adoptive transfer of granzyme B–deficient Treg cells prevented GVHD lethality, suppressed serum cytokine production in vivo, and prevented target organ damage. These data contrast strikingly with our previous study, which demonstrated that granzyme B plays a nonredundant role in Treg cell–mediated suppression of antitumor responses. Taken together, these findings suggest that targeting specific Treg cell–suppressive mechanisms, such as granzyme B, may be therapeutically beneficial for segregating GVHD and graft-versus-tumor immune responses.

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