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  1. Article ; Online: Disabled C3ar1/C5ar1 Signaling in Foxp3+ T Regulatory Cells Leads to TSDR Demethylation and Long-Term Stability.

    Medof, M Edward / Rieder, Sadiye A / Shevach, Ethan M

    Journal of immunology (Baltimore, Md. : 1950)

    2023  Volume 211, Issue 9, Page(s) 1359–1366

    Abstract: Demethylation of the T regulatory cell (Treg)-specific demethylation region (TSDR) of the Foxp3 gene is the hallmark of Foxp3+ Treg stability, but the cellular signaling that programs this epigenetic state remains undefined. In this article, we show that ...

    Abstract Demethylation of the T regulatory cell (Treg)-specific demethylation region (TSDR) of the Foxp3 gene is the hallmark of Foxp3+ Treg stability, but the cellular signaling that programs this epigenetic state remains undefined. In this article, we show that suppressed C3a and C5a receptor (C3ar1/C5ar1) signaling in murine Tregs plays an obligate role. Murine C3ar1-/-C5ar1-/- Foxp3+ cells showed increased suppressor of cytokine signaling 1/2/3 expression, vitamin C stabilization, and ten-eleven translocation (TET) 1, TET2, and TET3 expression, all of which are linked to Treg stability. C3ar1-/-C5ar1-/- Foxp3+ cells additionally were devoid of BRD4 signaling that primes Th17 cell lineage commitment. Orally induced OVA-specific C3ar1-/-C5ar1-/- Foxp3+ OT-II Tregs transferred to OVA-immunized wild-type recipients remained >90% Foxp3+ out to 4 mo, whereas identically generated CD55-/- (DAF-/-) Foxp3+ OT-II Tregs (in which C3ar1/C5ar1 signaling is potentiated) lost >75% of Foxp3 expression by 14 d. After 4 mo in vivo, the C3ar1-/-C5ar1-/- Foxp3+ OT-II Tregs fully retained Foxp3 expression even with OVA challenge and produced copious TGF-β and IL-10. Their TSDR was demethylated comparably with that of thymic Tregs. They exhibited nuclear translocation of NFAT and NF-κB reported to stabilize thymic Tregs by inducing hairpin looping of the TSDR to the Foxp3 promoter. Thus, disabled CD4+ cell C3ar1/C5ar1 signaling triggers the sequential cellular events that lead to demethylation of the Foxp3 TSDR.
    MeSH term(s) Mice ; Animals ; T-Lymphocytes, Regulatory ; DNA Methylation ; Transcription Factors/metabolism ; Gene Expression Regulation ; Receptor, Anaphylatoxin C5a/metabolism ; Nuclear Proteins/genetics ; Demethylation ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism
    Chemical Substances Transcription Factors ; Receptor, Anaphylatoxin C5a ; Nuclear Proteins ; Forkhead Transcription Factors ; Foxp3 protein, mouse ; C5ar1 protein, mouse
    Language English
    Publishing date 2023-09-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Research Support, N.I.H., Extramural
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.2300184
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  2. Article: Foxp3

    Shevach, Ethan M

    Frontiers in immunology

    2018  Volume 9, Page(s) 1048

    Abstract: T regulatory (Treg) cells were discovered more than 20 years ago and have remained a topic of intense investigation by immunologists. The initial doubts about their existence were dissipated by the discovery in 2003 of the lineage specific transcription ... ...

    Abstract T regulatory (Treg) cells were discovered more than 20 years ago and have remained a topic of intense investigation by immunologists. The initial doubts about their existence were dissipated by the discovery in 2003 of the lineage specific transcription factor Foxp3. In this article, I will discuss some of the questions that I believe still need to be answered before we will be able to fully apply Treg therapy to the clinic. The major issue that remains to be resolved is how they mediate their suppressive functions. In order to correct defective suppression in autoimmune disease (assuming it is a causative factor) or to augment suppression in graft versus host disease or during organ transplantation, we still need to fully understand the biochemical nature of suppressor mechanisms. Similarly, in cancer, it is now widely accepted that reversal of Treg suppression would be highly desirable, yet which of the many purported pathways of suppression are operative in different tumors in different anatomic sites. Many of the concepts we have developed are based on
    MeSH term(s) Autoimmune Diseases/immunology ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/immunology ; Graft vs Host Disease ; Humans ; Immunosuppressive Agents ; Organ Transplantation ; T-Lymphocytes, Regulatory/immunology
    Chemical Substances FOXP3 protein, human ; Forkhead Transcription Factors ; Immunosuppressive Agents
    Language English
    Publishing date 2018-05-15
    Publishing country Switzerland
    Document type Journal Article ; Personal Narrative ; Research Support, N.I.H., Intramural ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2018.01048
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Control of regulatory T cell homeostasis.

    Buszko, Maja / Shevach, Ethan M

    Current opinion in immunology

    2020  Volume 67, Page(s) 18–26

    Abstract: ... ...

    Abstract CD4
    MeSH term(s) Animals ; Cytokines/immunology ; Homeostasis/immunology ; Humans ; Receptors, Antigen, T-Cell/immunology ; T-Lymphocytes, Regulatory/immunology
    Chemical Substances Cytokines ; Receptors, Antigen, T-Cell
    Language English
    Publishing date 2020-08-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1035767-1
    ISSN 1879-0372 ; 0952-7915
    ISSN (online) 1879-0372
    ISSN 0952-7915
    DOI 10.1016/j.coi.2020.07.001
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  4. Article ; Online: Control of Memory Phenotype T Lymphocyte Homeostasis: Role of Costimulation.

    Panda, Abir K / Kim, Yong-Hee / Shevach, Ethan M

    Journal of immunology (Baltimore, Md. : 1950)

    2022  Volume 208, Issue 4, Page(s) 851–860

    Abstract: ... ...

    Abstract Foxp3
    MeSH term(s) Animals ; B7-1 Antigen/metabolism ; B7-2 Antigen/metabolism ; CD28 Antigens/metabolism ; CTLA-4 Antigen/antagonists & inhibitors ; CTLA-4 Antigen/metabolism ; Cytokines/metabolism ; Homeostasis/immunology ; Immune Checkpoint Inhibitors/pharmacology ; Lymphocyte Activation/drug effects ; Lymphocyte Activation/genetics ; Lymphocyte Activation/immunology ; Memory T Cells/immunology ; Memory T Cells/metabolism ; Mice ; Mice, Knockout ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Programmed Cell Death 1 Receptor/metabolism ; Signal Transduction ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism
    Chemical Substances B7-1 Antigen ; B7-2 Antigen ; CD28 Antigens ; CTLA-4 Antigen ; CTLA4 protein, human ; Cytokines ; Immune Checkpoint Inhibitors ; Programmed Cell Death 1 Receptor
    Language English
    Publishing date 2022-01-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.2100653
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Garp as a therapeutic target for modulation of T regulatory cell function.

    Shevach, Ethan M

    Expert opinion on therapeutic targets

    2017  Volume 21, Issue 2, Page(s) 191–200

    Abstract: Introduction: ... ...

    Abstract Introduction: Foxp3
    MeSH term(s) Animals ; Autoimmunity/immunology ; Forkhead Transcription Factors/immunology ; Humans ; Immunotherapy/methods ; Inflammation/immunology ; Inflammation/therapy ; Integrins/metabolism ; Membrane Proteins/immunology ; Mice ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/therapy ; T-Lymphocytes, Regulatory/immunology ; Transforming Growth Factor beta/immunology ; Transforming Growth Factor beta1/immunology
    Chemical Substances FOXP3 protein, human ; Forkhead Transcription Factors ; Integrins ; LRRC32 protein, human ; Membrane Proteins ; Transforming Growth Factor beta ; Transforming Growth Factor beta1
    Language English
    Publishing date 2017-02
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2055208-7
    ISSN 1744-7631 ; 1472-8222
    ISSN (online) 1744-7631
    ISSN 1472-8222
    DOI 10.1080/14728222.2017.1275568
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  6. Article ; Online: Regulatory T cells: Master thieves of the immune system.

    Akkaya, Billur / Shevach, Ethan M

    Cellular immunology

    2020  Volume 355, Page(s) 104160

    Abstract: Treg cells are the immune system's in-house combatants against pathological immune activation. Because they are vital to maintenance of peripheral tolerance, it is important to understand how they perform their functions. To this end, various mechanisms ... ...

    Abstract Treg cells are the immune system's in-house combatants against pathological immune activation. Because they are vital to maintenance of peripheral tolerance, it is important to understand how they perform their functions. To this end, various mechanisms have been proposed for Treg-mediated immune inhibition. A major group of mechanisms picture Treg cells as skilled thieves stealing a plethora of molecules that would otherwise promote immune effector functions. This suggests that several million years of evolution have endowed Treg cells with efficient ways to deprive immune effectors of activating stimuli to prevent immunopathology for survival of the host. Although we are still long way from deciphering their complete set of tricks, this review will focus on the types of "crimes" committed by these master thieves in both secondary lymphoid organs and non-lymphoid tissue.
    MeSH term(s) Animals ; Cytokines/immunology ; Forkhead Transcription Factors/metabolism ; Humans ; Immune Tolerance/immunology ; Immunity/immunology ; Peripheral Tolerance/immunology ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; T-Lymphocytes, Regulatory/physiology
    Chemical Substances Cytokines ; FOXP3 protein, human ; Forkhead Transcription Factors
    Language English
    Publishing date 2020-07-11
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Review
    ZDB-ID 80094-6
    ISSN 1090-2163 ; 0008-8749
    ISSN (online) 1090-2163
    ISSN 0008-8749
    DOI 10.1016/j.cellimm.2020.104160
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  7. Article ; Online: Helios: still behind the clouds.

    Thornton, Angela M / Shevach, Ethan M

    Immunology

    2019  Volume 158, Issue 3, Page(s) 161–170

    Abstract: Regulatory T (Treg) cells are a subset of ... ...

    Abstract Regulatory T (Treg) cells are a subset of CD4
    MeSH term(s) Animals ; Antigens, Differentiation/immunology ; DNA-Binding Proteins/immunology ; Forkhead Transcription Factors/immunology ; Humans ; Ikaros Transcription Factor/immunology ; Mice ; T-Lymphocytes, Regulatory/immunology ; Transcription Factors/immunology
    Chemical Substances Antigens, Differentiation ; DNA-Binding Proteins ; FOXP3 protein, human ; Forkhead Transcription Factors ; Foxp3 protein, mouse ; IKZF2 protein, human ; Transcription Factors ; Zfpn1a2 protein, mouse ; Ikaros Transcription Factor (148971-36-2)
    Language English
    Publishing date 2019-10-13
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Review
    ZDB-ID 80124-0
    ISSN 1365-2567 ; 0019-2805 ; 0953-4954
    ISSN (online) 1365-2567
    ISSN 0019-2805 ; 0953-4954
    DOI 10.1111/imm.13115
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  8. Article: Illuminating T cell-dendritic cell interactions in vivo by FlAsHing antigens.

    Akkaya, Munir / Al Souz, Jafar / Williams, Daniel / Kamdar, Rahul / Kamenyeva, Olena / Kabat, Juraj / Shevach, Ethan M / Akkaya, Billur

    Research square

    2023  

    Abstract: Delineating the complex network of interactions between antigen-specific T cells and antigen presenting cells (APCs) is crucial for effective precision therapies against cancer, chronic infections, and autoimmunity. However, the existing arsenal for ... ...

    Abstract Delineating the complex network of interactions between antigen-specific T cells and antigen presenting cells (APCs) is crucial for effective precision therapies against cancer, chronic infections, and autoimmunity. However, the existing arsenal for examining antigen-specific T cell interactions is restricted to a select few antigen-T cell receptor pairs, with limited in situ utility. This lack of versatility is largely due to the disruptive effects of reagents on the immune synapse, which hinder real-time monitoring of antigen-specific interactions. To address this limitation, we have developed a novel and versatile immune monitoring strategy by adding a short cysteine-rich tag to antigenic peptides that emits fluorescence upon binding to thiol-reactive biarsenical hairpin compounds. Our findings demonstrate the specificity and durability of the novel antigen-targeting probes during dynamic immune monitoring in vitro and in vivo. This strategy opens new avenues for biological validation of T-cell receptors with newly identified epitopes by revealing the behavior of previously unrecognized antigen-receptor pairs, expanding our understanding of T cell responses.
    Language English
    Publishing date 2023-12-21
    Publishing country United States
    Document type Preprint
    DOI 10.21203/rs.3.rs-3193191/v3
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  9. Article: Tregs, Helios and tumor immunity: the sun has not yet risen.

    Thornton, Angela M / Shevach, Ethan M

    Translational cancer research

    2016  Volume 5, Issue Suppl 4, Page(s) S672–S674

    Language English
    Publishing date 2016-12-27
    Publishing country China
    Document type Journal Article ; Comment
    ZDB-ID 2901601-0
    ISSN 2219-6803 ; 2218-676X
    ISSN (online) 2219-6803
    ISSN 2218-676X
    DOI 10.21037/tcr.2016.10.47
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  10. Article ; Online: Corrigendum to "Selective deletion of Eos (Ikzf4) in T-regulatory cells leads to loss of suppressive function and development of systemic autoimmunity" [J. Autoimmun. 105C (2019) 102300].

    Gokhale, Ameya S / Gangaplara, Arunakumar / Lopez-Occasio, Maria / Thornton, Angela M / Shevach, Ethan M

    Journal of autoimmunity

    2020  Volume 114, Page(s) 102544

    Language English
    Publishing date 2020-09-24
    Publishing country England
    Document type Published Erratum
    ZDB-ID 639452-8
    ISSN 1095-9157 ; 0896-8411
    ISSN (online) 1095-9157
    ISSN 0896-8411
    DOI 10.1016/j.jaut.2020.102544
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