Interruption of thymic activity in adults improves responses to tumor immunotherapy

AbstractThe thymus produces precursors of both effectors and regulatory T cells (Tconv and Treg, respectively) whose interactions prevents autoimmunity while allowing efficient protective immune responses. Tumors express a composite of self- and tumor-specific antigens and engage both Tconv and Treg cells. Along the aging process, the thymus involutes, and tumor incidence increases, a correlation proposed previously to be causal and the result of effector cell decline. In this work, we directly tested whether interruption of thymic activity in adult mice affects Foxp3 expressing Treg composition and function, and alters tumor immune surveillance. Young adult mice, on two different genetic backgrounds, were surgically thymectomized (TxT) and analyzed or challenged 2 months later. Cellular analysis revealed a 10-fold decrease in both Tconv and Treg numbers and a bias for activated cells. The persisting Treg displayed reduced stability of Foxp3 expression and, as a population, showed compromised return to homeostasis upon induced perturbations. We next tested the growth of three tumor models from different origin and presenting distinct degrees of spontaneous immunogenicity. In none of these conditions adult TxT facilitated tumor growth. Rather TxT enhanced the efficacy of anti-tumor immunotherapies targeting Treg and/or the checkpoint CTLA4, as evidenced by increased frequency of responder mice and decreased intra-tumoral Treg to CD8+IFNγ+ cell ratio. Together, our findings point to a scenario where abrogation of thymic activities affects preferentially the regulatory over the ridding arm of the immune activities elicited by tumors, and argues that higher incidence of tumors with age cannot be solely attributed to thymic output decline.

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FOXP3 Expression in B and T Cell Lymphomas.

Blood ◽

10.1182/blood.v106.11.4503.4503 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4503-4503

Author(s):

Giovanna Roncador ◽

Juan Fernando Garcia ◽

Jose Francisco Garcia ◽

Lorena Maestre ◽

Elena Lucas ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory Gene ◽

Immune Surveillance ◽

Foxp3 Expression ◽

Treg Cells ◽

Cell Leukaemia ◽

Tissue Sections ◽

T Cell Lymphomas ◽

And Function

Abstract Foxp3, which encodes a forkhead/winged helix transcription factor designated Scurfin, is a key regulatory gene required for the development and function of regulatory CD4+CD25+ T cells (Treg), a subpopulation of T-cells specialized in maintaining the balance between immunity and tolerance. Humans with defects in the FOXP3 gene, develop strong activation of the immune system, leading to multiorgan autoimmune disease, allergies, inflammatory bowel disease and severe infections, collectively known as the IPEX syndrome (immune deregulation, polyendocrinopathy, enteropathy, X-linked inheritance syndrome) Because of the importance of FOXP3 in the development and function of Treg cells, and its potential use as a specific Treg marker, we have developed several monoclonal antibodies against FOXP3, for use on paraffin-embedded tissue sections and evaluated its expression in a large series (150 cases) of B- and T-cell lymphomas. In reactive lymphoid tissue, strong nuclear FOXP3 expression was observed in approximately 5% of interfollicular T-cells. FOXP3 expression in tumour cells was confined to most of Adult T-cell Leukaemia/Lymphoma (ATLL) cases (68%), with some variability in protein expression. In other lymphoma types, FOXP3 expression was only detected in the reactive T-cell background, and the number of FOXP3-positive reactive T-cells was variable, ranging from almost a complete absence (Burkitt’s lymphoma) to abundant infiltrate (common in follicular lymphoma). In conclusion, the availability of a FOXP3 monoclonal antibody, not only provides an important tool for the study of the development and function of Treg cells, but also represents a useful marker for the identification of ATLL cases in formalin-fixed paraffin-embedded tissue sections. The presence or absence of Treg cells in the tumour environment could also play a role in the immune surveillance of tumours, thus implying a potential additional value for the detection of this cell population in tumour samples.

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

Cellular and Molecular Immunology ◽

10.1038/s41423-020-00599-z ◽

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.

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Tolerogenic Splenic IDO+Dendritic Cells from the Mice Treated with Induced-Treg Cells Suppress Collagen-Induced Arthritis

Journal of Immunology Research ◽

10.1155/2014/831054 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 9

Author(s):

Jie Yang ◽

Yiming Yang ◽

Huahua Fan ◽

Hejian Zou

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Foxp3 Expression ◽

Treated Group ◽

Treg Cells ◽

Therapeutic Effects ◽

Dependent Manner ◽

Collagen Induced Arthritis

TGF-β-induced regulatory T cells (iTregs) retain Foxp3 expression and immune-suppressive activity in collagen-induced arthritis (CIA). However, the mechanisms whereby transferred iTregs suppress immune responses, particularly the interplay between iTregs and dendritic cells (DCs)in vivo, remain incompletely understood. In this study, we found that after treatment with iTregs, splenic CD11c+DCs, termed “DCiTreg,” expressed tolerogenic phenotypes, secreted high levels of IL-10, TGF-β, and IDO, and showed potent immunosuppressive activityin vitro. After reinfusion with DCiTreg, marked antiarthritic activity improved clinical scores and histological end-points were observed. The serological levels of inflammatory cytokines and anti-CII antibodies were low and TGF-βproduction was high in the DCiTreg-treated group. DCiTregalso induced new iTregsin vivo. Moreover, the inhibitory activity of DCiTregon CIA was lost following pretreatment with the inhibitor of indoleamine 2,3-dioxygenase (IDO). Collectively, these findings suggest that transferred iTregs could induce tolerogenic characteristics in splenic DCs and these cells could effectively dampen CIA in an IDO-dependent manner. Thus, the potential therapeutic effects of iTregs in CIA are likely maintained through the generation of tolerogenic DCsin vivo.

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Antigen-specific Treg cells in immunological tolerance: implications for allergic diseases

F1000Research ◽

10.12688/f1000research.12650.1 ◽

2018 ◽

Vol 7 ◽

pp. 38 ◽

Cited By ~ 11

Author(s):

Azza Abdel-Gadir ◽

Amir H. Massoud ◽

Talal A. Chatila

Keyword(s):

Immune Responses ◽

Treg Cell ◽

Allergic Diseases ◽

Treg Cells ◽

Immunological Tolerance ◽

Inflammatory Disorders ◽

Cell Responses ◽

Recent Advances ◽

And Function ◽

Is Failure

Allergic diseases are chronic inflammatory disorders in which there is failure to mount effective tolerogenic immune responses to inciting allergens. The alarming rise in the prevalence of allergic diseases in recent decades has spurred investigations to elucidate the mechanisms of breakdown in tolerance in these disorders and means of restoring it. Tolerance to allergens is critically dependent on the generation of allergen-specific regulatory T (Treg) cells, which mediate a state of sustained non-responsiveness to the offending allergen. In this review, we summarize recent advances in our understanding of mechanisms governing the generation and function of allergen-specific Treg cells and their subversion in allergic diseases. We will also outline approaches to harness allergen-specific Treg cell responses to restore tolerance in these disorders.

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Homeobox protein Hhex negatively regulates Treg cells by inhibiting Foxp3 expression and function

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1907224116 ◽

2019 ◽

Vol 116 (51) ◽

pp. 25790-25799 ◽

Cited By ~ 5

Author(s):

Sung Woong Jang ◽

Soo Seok Hwang ◽

Hyeong Su Kim ◽

Min Kyung Kim ◽

Woo Ho Lee ◽

...

Keyword(s):

Essential Role ◽

Foxp3 Expression ◽

Treg Cells ◽

Negative Regulator ◽

Delayed Type Hypersensitivity ◽

Type I ◽

Signature Genes ◽

Homeobox Protein ◽

The Stability ◽

And Function

Regulatory T (Treg) cells play an essential role in maintaining immune homeostasis, but the suppressive function of Treg cells can be an obstacle in the treatment of cancer and chronic infectious diseases. Here, we identified the homeobox protein Hhex as a negative regulator of Treg cells. The expression of Hhex was lower in Treg cells than in conventional T (Tconv) cells. Hhex expression was repressed in Treg cells by TGF-β/Smad3 signaling. Retroviral overexpression of Hhex inhibited the differentiation of induced Treg (iTreg) cells and the stability of thymic Treg (tTreg) cells by significantly reducing Foxp3 expression. Moreover, Hhex-overexpressing Treg cells lost their immunosuppressive activity and failed to prevent colitis in a mouse model of inflammatory bowel disease (IBD).Hhexexpression was increased; however,Foxp3expression was decreased in Treg cells in a delayed-type hypersensitivity (DTH) reaction, a type I immune reaction. Hhex directly bound to the promoters ofFoxp3and other Treg signature genes, includingIl2raandCtla4, and repressed their transactivation. The homeodomain and N-terminal repression domain of Hhex were critical for inhibiting Foxp3 and other Treg signature genes. Thus, Hhex plays an essential role in inhibiting Treg cell differentiation and function via inhibition of Foxp3.

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Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+ regulatory T-cells

Molecular Biology of the Cell ◽

10.1091/mbc.e14-08-1323 ◽

2015 ◽

Vol 26 (15) ◽

pp. 2845-2857 ◽

Cited By ~ 51

Author(s):

Magdalena Walecki ◽

Florian Eisel ◽

Jörg Klug ◽

Nelli Baal ◽

Agnieszka Paradowska-Dogan ◽

...

Keyword(s):

T Cells ◽

Androgen Receptor ◽

Treg Cell ◽

Foxp3 Expression ◽

Treg Cells ◽

Strong Increase ◽

Histone H4 ◽

And Function

CD4+CD25+Foxp3+ regulatory T (Treg) cells are able to inhibit proliferation and cytokine production in effector T-cells and play a major role in immune responses and prevention of autoimmune disease. A master regulator of Treg cell development and function is the transcription factor Foxp3. Several cytokines, such as TGF-β and IL-2, are known to regulate Foxp3 expression as well as methylation of the Foxp3 locus. We demonstrated previously that testosterone treatment induces a strong increase in the Treg cell population both in vivo and in vitro. Therefore we sought to investigate the direct effect of androgens on expression and regulation of Foxp3. We show a significant androgen-dependent increase of Foxp3 expression in human T-cells from women in the ovulatory phase of the menstrual cycle but not from men and identify a functional androgen response element within the Foxp3 locus. Binding of androgen receptor leads to changes in the acetylation status of histone H4, whereas methylation of defined CpG regions in the Foxp3 gene is unaffected. Our results provide novel evidence for a modulatory role of androgens in the differentiation of Treg cells.

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Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1421463112 ◽

2015 ◽

Vol 112 (25) ◽

pp. E3246-E3254 ◽

Cited By ~ 58

Author(s):

Yayi Gao ◽

Jiayou Tang ◽

Weiqian Chen ◽

Qiang Li ◽

Jia Nie ◽

...

Keyword(s):

Molecular Mechanisms ◽

Cell Function ◽

Inflammatory Diseases ◽

Foxp3 Expression ◽

Treg Cells ◽

Autoimmune Encephalomyelitis ◽

Inflammatory Conditions ◽

Forkhead Box ◽

Binding Partners ◽

And Function

Forkhead box P3 (FOXP3)-positive Treg cells are crucial for maintaining immune homeostasis. FOXP3 cooperates with its binding partners to elicit Treg cells’ signature and function, but the molecular mechanisms underlying the modulation of the FOXP3 complex remain unclear. Here we report that Deleted in breast cancer 1 (DBC1) is a key subunit of the FOXP3 complex. We found that DBC1 interacts physically with FOXP3, and depletion of DBC1 attenuates FOXP3 degradation in inflammatory conditions. Treg cells from Dbc1-deficient mice were more resistant to inflammation-mediated abrogation of Foxp3 expression and function and delayed the onset and severity of experimental autoimmune encephalomyelitis and colitis in mice. These findings establish a previously unidentified mechanism regulating FOXP3 stability during inflammation and reveal a pathway for potential therapeutic modulation and intervention in inflammatory diseases.

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Critical Roles of Balanced T Helper 9 Cells and Regulatory T Cells in Allergic Airway Inflammation and Tumor Immunity

Journal of Immunology Research ◽

10.1155/2021/8816055 ◽

2021 ◽

Vol 2021 ◽

pp. 1-20

Author(s):

Muhua Huang ◽

Jingcheng Dong

Keyword(s):

T Cells ◽

Immune Responses ◽

Airway Inflammation ◽

Tumor Immunity ◽

Allergic Airway Inflammation ◽

Treg Cells ◽

T Helper ◽

Th Cells ◽

Th9 Cells ◽

And Function

CD4+T helper (Th) cells are important mediators of immune responses in asthma and cancer. When counteracted by different classes of pathogens, naïve CD4+T cells undergo programmed differentiation into distinct types of Th cells. Th cells orchestrate antigen-specific immune responses upon their clonal T-cell receptor (TCR) interaction with the appropriate peptide antigen presented on MHC class II molecules expressed by antigen-presenting cells (APCs). T helper 9 (Th9) cells and regulatory T (Treg) cells and their corresponding cytokines have critical roles in tumor and allergic immunity. In the context of asthma and cancer, the dynamic internal microenvironment, along with chronic inflammatory stimuli, influences development, differentiation, and function of Th9 cells and Treg cells. Furthermore, the dysregulation of the balance between Th9 cells and Treg cells might trigger aberrant immune responses, resulting in development and exacerbation of asthma and cancer. In this review, the development, differentiation, and function of Th9 cells and Treg cells, which are synergistically regulated by various factors including cytokine signals, transcriptional factors (TFs), costimulatory signals, microenvironment cues, metabolic pathways, and different signal pathways, will be discussed. In addition, we focus on the recent progress that has helped to achieve a better understanding of the roles of Th9 cells and Treg cells in allergic airway inflammation and tumor immunity. We also discuss how various factors moderate their responses in asthma and cancer. Finally, we summarize the recent findings regarding potential mechanisms for regulating the balance between Th9 and Treg cells in asthma and cancer. These advances provide opportunities for novel therapeutic strategies that are aimed at reestablishing the balance of these cells in the diseases.

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The liver: a model of organ-specific lymphocyte recruitment

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399402004155 ◽

2002 ◽

Vol 4 (2) ◽

pp. 1-15 ◽

Cited By ~ 51

Author(s):

Trish Lalor ◽

David Adams

Keyword(s):

Immune Responses ◽

Portal Vein ◽

Immune Surveillance ◽

Hepatic Veins ◽

Physical Conditions ◽

Food Antigens ◽

Bile Ductule ◽

Organ Specific ◽

And Function ◽

Portal Tracts

The liver is constantly exposed to gut-derived antigens that enter via the portal vein, and it must modulate immune responses so that harmful pathogens are cleared but necessary food antigens are ignored. The liver contains a large resident and migratory population of lymphocytes and macrophages that provide immune surveillance against foreign antigen. This population of cells can be rapidly expanded in response to infection or injury by recruiting leukocytes from the circulation, a process that is dependent on the ability of lymphocytes to recognise, bind to and migrate across the endothelial cells that line the vasculature. Lymphocytes can enter the liver at several sites: the vascular endothelium in the portal tracts (comprising the hepatic artery, portal vein and bile ductule), the sinusoids (through which the blood percolates past the hepatocytes) or the central hepatic veins (through which the blood exits). The requirements and physical conditions at each site vary and there is evidence that different combinations of adhesion proteins are involved at these different sites. This article discusses the expression and function of adhesion molecules within the liver and demonstrates how specific populations of effector lymphocytes can be selectively recruited to the liver.

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Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production

Blood ◽

10.1182/blood-2006-01-0329 ◽

2006 ◽

Vol 108 (1) ◽

pp. 390-399 ◽

Cited By ~ 352

Author(s):

Robert Zeiser ◽

Vu H. Nguyen ◽

Andreas Beilhack ◽

Martin Buess ◽

Stephan Schulz ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Cell Function ◽

Interleukin 2 ◽

Foxp3 Expression ◽

Treg Cells ◽

Treg Function ◽

Functional Defect ◽

In Vivo Bioluminescence Imaging

CD4+CD25+ regulatory T (Treg) cells control immunologic tolerance and antitumor immune responses. Therefore, in vivo modification of Treg function by immunosuppressant drugs has broad implications for transplantation biology, autoimmunity, and vaccination strategies. In vivo bioluminescence imaging demonstrated reduced early proliferation of donor-derived luciferase-labeled conventional T cells in animals treated with Treg cells after major histocompatibility complex mismatch bone marrow transplantation. Combining Treg cells with cyclosporine A (CSA), but not rapamycin (RAPA) or mycophenolate mofetil (MMF), suppressed Treg function assessed by increased T-cell proliferation, graft-versus-host disease (GVHD) severity, and reduced survival. Expansion of Treg and FoxP3 expression within this population was lowest in conjunction with CSA, suggesting that calcineurin-dependent interleukin 2 (IL-2) production is critically required for Treg cells in vivo. The functional defect of Treg cells after CSA exposure could be reversed by exogenous IL-2. Further, the Treg plus RAPA combination preserved graft-versus-tumor (GVT) effector function against leukemia cells. Our data indicate that RAPA and MMF rather than CSA preserve function of Treg cells in pathologic immune responses such as GVHD without weakening the GVT effect. (Blood. 2006;108:390-399)

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