CD4+CD25−LAG3+regulatory T cells controlled by the transcription factor Egr-2

Okamura, Tomohisa; Fujio, Keishi; Shibuya, Masatoyo; Sumitomo, Shuji; Shoda, Hirofumi; Sakaguchi, Shimon; Yamamoto, Kazuhiko

doi:10.1073/pnas.0906872106

Cited by 190 publications

(208 citation statements)

References 52 publications

(59 reference statements)

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“…After 48-h stimulation with anti-CD3 mAb alone or anti-CD3/ anti-CD28 mAb, Egr-2-or Egr-3-transduced CD4 + T cells were sorted according to the intensity of their GFP expression. Similar to our previous observation that Egr-2 induces LAG3 and IL-10 expression in CD4 + T cells (20), quantitative PCR showed that Egr-3 induced the mRNA expression of IL-10 ( Fig. 1A) and LAG3 (Fig.…”

Section: Resultssupporting

confidence: 74%

“…We examined Egr-3-expressing murine CD4 + T cells to identify TGF-b1-producing T cell populations with regulatory activity, but no specific signal of Egr-3 expression could be detected in murine CD4 + T cells. Although we identified Egr-2-expressing CD4 + CD25 2 LAG3 + T cells in mice (20), these CD4 + CD25 2 LAG3 + T cells did not show increased egr3 expression compared with naive CD4 + T cells.…”

Section: Egr-3 Suppresses Ag-specific T Cell Responses Via Tgf-b1mentioning

confidence: 82%

“…TCRinduced Egr-1 and NGFI-A-binding protein 2 enhance T cell function, and Egr-2 and Egr-3 inhibit T cell function via the suppression of Egr-1 and NGFI-A-binding protein 2 expression (19). We have previously reported that Egr-2 is specifically expressed in IL-10-producing CD4 + CD25 2 lymphocyte activation gene 3 (LAG3) + Tregs and that Egr-2 confers IL-10 and LAG3 expression and in vivo regulatory activity on CD4 + T cells (20).…”

mentioning

confidence: 99%

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Transcription Factor Early Growth Response 3 Is Associated with the TGF-β1 Expression and the Regulatory Activity of CD4-Positive T Cells In Vivo

Sumitomo

Fujio

Okamura

et al. 2013

The Journal of Immunology

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TGF-β1 is an important anti-inflammatory cytokine, and several regulatory T cell (Treg) subsets including CD4+CD25+Foxp3+ Tregs and Th3 cells have been reported to exert regulatory activity via the production of TGF-β1. However, it has not yet been elucidated which transcription factor is involved in TGF-β1 transcription. Early growth response 3 (Egr-3) is a zinc-finger transcription factor that creates and maintains T cell anergy. In this study, we found that Egr-3 induces the expression of TGF-β1 in both murine and human CD4+ T cells. Egr-3 overexpression in murine CD4+ T cells induced the production of TGF-β1 and enhanced the phosphorylation of STAT3, which is associated with TGF-β1 transcription. Moreover, Egr-3 conferred Ag-specific regulatory activity on murine CD4+ T cells. In collagen-induced arthritis and delayed-type hypersensitivity model mice, Egr-3–transduced CD4+ T cells exhibited significant regulatory activity in vivo. In particular, the suppression of delayed-type hypersensitivity depended on TGF-β1. In human tonsils, we found that CD4+CD25−CD45RO−lymphocyte activation gene 3 (LAG3)− T cells express membrane-bound TGF-β1 in an EGR3-dependent manner. Gene-expression analysis revealed that CD4+CD25−CD45RO−LAG3− T cells are quite different from conventional CD4+CD25+Foxp3+ Tregs. Intriguingly, the CD4+CD25−CD45RO−LAG3− T cells suppressed graft-versus-host disease in immunodeficient mice transplanted with human PBMCs. Our results suggest that Egr-3 is a transcription factor associated with TGF-β1 expression and in vivo regulatory activity in both mice and humans.

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Section: Resultssupporting

confidence: 74%

Section: Egr-3 Suppresses Ag-specific T Cell Responses Via Tgf-b1mentioning

confidence: 82%

mentioning

confidence: 99%

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Transcription Factor Early Growth Response 3 Is Associated with the TGF-β1 Expression and the Regulatory Activity of CD4-Positive T Cells In Vivo

Sumitomo

Fujio

Okamura

et al. 2013

The Journal of Immunology

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“…3B, all of the CD4 + T cells expressed LAG3 following CD26 or CD28 costimulation, and no difference was observed in the percentage of LAG3-expressing cells, whereas the expression intensity of LAG3 after CD26-mediated costimulation was higher than after CD28-mediated costimulation. LAG3 also serves as a marker of IL-10-producing Tregs (25), suggesting that signaling events via CD26 may induce the development of CD4 + T cells to a Tr1-like phenotype.…”

Section: Cd26-mediated Costimulation Induces the Development Of Cd4 +mentioning

confidence: 99%

“…Type 1 Tregs (Tr1s) are characterized by high-level production of IL-10 with regulatory activity (24). Lymphocyte-activation gene 3 (LAG3) and early growth response 2 (EGR2) have been recently reported as markers of Tr1-like cells (25). LAG3 binds to MHC class II molecules with higher affinity than CD4, leading to transduction of inhibitory signals for both T cells and APCs (26,27).…”

mentioning

confidence: 99%

CD26-Mediated Induction of EGR2 and IL-10 as Potential Regulatory Mechanism for CD26 Costimulatory Pathway

Hatano

Ohnuma

Otsuka

et al. 2015

The Journal of Immunology

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CD26 is associated with T cell signal transduction processes as a costimulatory molecule, and CD26+ T cells have been suggested to be involved in the pathophysiology of diverse autoimmune diseases. Although the cellular and molecular mechanisms involved in CD26-mediated T cell activation have been extensively evaluated by our group and others, potential negative feedback mechanisms to regulate CD26-mediated activation still remain to be elucidated. In the present study, we examine the expression of inhibitory molecules induced via CD26-mediated costimulation. We show that coengagement of CD3 and CD26 induces preferential production of IL-10 in human CD4+ T cells, mediated through NFAT and Raf-MEK-ERK pathways. A high level of early growth response 2 (EGR2) is also induced following CD26 costimulation, possibly via NFAT and AP-1–mediated signaling, and knockdown of EGR2 leads to decreased IL-10 production. Furthermore, CD3/CD26-stimulated CD4+ T cells clearly suppress proliferative activity and effector cytokine production of bystander T cells in an IL-10–dependent manner. Taken together, our data suggest that robust CD26 costimulatory signaling induces preferential expression of EGR2 and IL-10 as a potential mechanism for regulating CD26-mediated activation.

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Depletion of LAG‐3⁺ T Cells Translated to Pharmacology and Improvement in Psoriasis Disease Activity: A Phase I Randomized Study of mAb GSK2831781

Ellis

Marks

Srinivasan

et al. 2020

Clin Pharma and Therapeutics

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Activated T cells drive a range of immune-mediated inflammatory diseases. LAG-3 is transiently expressed on recently activated CD4 + and CD8 + T cells. We describe the engineering and first-inhuman clinical study (NCT02195349) of GSK2831781 (an afucosylated humanized IgG1 monoclonal antibody enhanced with high affinity for Fc receptors and LAG-3 and antibody-dependent cellular cytotoxicity capabilities), which depletes LAG-3 expressing cells. GSK2831781 was tested in a phase I/Ib, double-blind, placebo-controlled clinical study, which randomized 40 healthy participants (part A) and 27 patients with psoriasis (part B) to single doses of GSK2831781 (up to 0.15 and 5 mg/kg, respectively) or placebo. Adverse events were generally balanced across groups, with no safety or tolerability concern identified. LAG-3 + cell depletion in peripheral blood was observed at doses ≥ 0.15 mg/ kg and was dose-dependent. In biopsies of psoriasis plaques, a reduction in mean group LAG-3 + and CD3 + T-cell counts was observed following treatment. Downregulation of proinflammatory genes (IL-17A, IL-17F, IFNγ, and S100A12) and upregulation of the epithelial barrier integrity gene, CDHR1, was observed with the 5 mg/kg dose of GSK2831781. Psoriasis disease activity improved up to day 43 at all GSK2831781 doses (0.5, 1.5, and 5 mg/kg) compared with placebo. Depletion of LAG-3-expressing activated T cells is a novel approach, and this first clinical study shows that GSK2831781 is pharmacologically active and provides encouraging early evidence of clinical effects in psoriasis, which warrants further investigation in T-cell-mediated inflammatory diseases.

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CD4⁺CD25⁻LAG3⁺regulatory T cells controlled by the transcription factor Egr-2

Abstract: Regulatory T cells (Tregsanergy ͉ Blimp-1 ͉ inflammatory bowel disease ͉ IL-10 ͉ type 1 regulatory T cells

Cited by 190 publications

References 52 publications

Transcription Factor Early Growth Response 3 Is Associated with the TGF-β1 Expression and the Regulatory Activity of CD4-Positive T Cells In Vivo

Transcription Factor Early Growth Response 3 Is Associated with the TGF-β1 Expression and the Regulatory Activity of CD4-Positive T Cells In Vivo

CD26-Mediated Induction of EGR2 and IL-10 as Potential Regulatory Mechanism for CD26 Costimulatory Pathway

Depletion of LAG‐3⁺ T Cells Translated to Pharmacology and Improvement in Psoriasis Disease Activity: A Phase I Randomized Study of mAb GSK2831781

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CD4+CD25−LAG3+regulatory T cells controlled by the transcription factor Egr-2

Abstract: Regulatory T cells (Tregsanergy ͉ Blimp-1 ͉ inflammatory bowel disease ͉ IL-10 ͉ type 1 regulatory T cells

Cited by 190 publications

References 52 publications

Transcription Factor Early Growth Response 3 Is Associated with the TGF-β1 Expression and the Regulatory Activity of CD4-Positive T Cells In Vivo

Transcription Factor Early Growth Response 3 Is Associated with the TGF-β1 Expression and the Regulatory Activity of CD4-Positive T Cells In Vivo

CD26-Mediated Induction of EGR2 and IL-10 as Potential Regulatory Mechanism for CD26 Costimulatory Pathway

Depletion of LAG‐3+ T Cells Translated to Pharmacology and Improvement in Psoriasis Disease Activity: A Phase I Randomized Study of mAb GSK2831781

Contact Info

Product

Resources

About

CD4⁺CD25⁻LAG3⁺regulatory T cells controlled by the transcription factor Egr-2

Depletion of LAG‐3⁺ T Cells Translated to Pharmacology and Improvement in Psoriasis Disease Activity: A Phase I Randomized Study of mAb GSK2831781