CD4+CD25+Foxp3+regulatory T cells induce alternative activation of human monocytes/macrophages

Tiemessen, Machteld M.; Jagger, Ann; Evans, Hayley G.; Herwijnen, Martijn J. C. van; John, Susan; Taams, Leonie S.

doi:10.1073/pnas.0706832104

Cited by 733 publications

(580 citation statements)

References 37 publications

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“…Furthermore, Treg cells can also suppress innate immune cells. Treg cells inhibit both monocyte and neutrophil function,38 and induce an NK cell‐dependent endotoxin tolerance‐like phenomenon that is characterized by the decreased production of IFN‐γ 39. There is a large amount of evidence that patients with sepsis have increased numbers of Treg cells, which, by acting both on innate and adaptive immune cells, impair immunity and contribute to septic mortality.…”

Section: Mechanism Of Sepsis‐induced Immunosuppressionmentioning

confidence: 99%

Mechanisms of sepsis‐induced immunosuppression and immunological modification therapies for sepsis

Ono

Tsujimoto

Hiraki

et al. 2018

Annals of Gastroent Surgery

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Surgical injury can be a life‐threatening complication, not only due to the injury itself, but also due to immune responses to the injury and subsequent development of infections, which readily result in sepsis. Sepsis remains the leading cause of death in most intensive care units. Unfavorable outcomes of several high‐profile trials in the treatment of sepsis have led researchers to state that sepsis studies need a new direction. The immune response that occurs during sepsis is characterized by a cytokine‐mediated hyper‐inflammatory phase, which most patients survive, and a subsequent immunosuppressive phase. Therefore, therapies that improve host immunity might increase the survival of patients with sepsis. Many mechanisms are responsible for sepsis‐induced immunosuppression, including apoptosis of immune cells, increased regulatory T cells and expression of programmed cell death 1 on CD4+ T cells, and cellular exhaustion. Immunomodulatory molecules that were recently identified include interleukin‐7, interleukin‐15, and anti‐programmed cell death 1. Recent studies suggest that immunoadjuvant therapy is the next major advance in sepsis treatment.

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Section: Mechanism Of Sepsis‐induced Immunosuppressionmentioning

confidence: 99%

Mechanisms of sepsis‐induced immunosuppression and immunological modification therapies for sepsis

Ono

Tsujimoto

Hiraki

et al. 2018

Annals of Gastroent Surgery

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“…The interaction between Treg and macrophages is more complex. Treg can inhibit macrophage maturation and induce alternatively activated macrophages (AAM), which have regulatory capacity [34]. AAM are not efficient in antigen presentation and secrete anti-inflammatory cytokines such as IL-10.…”

Section: Macrophages But Not Nk Cells Are Critical For Pc61 Mab Activitymentioning

confidence: 99%

In vivo depletion of CD4⁺FOXP3⁺ Treg cells by the PC61 anti‐CD25 monoclonal antibody is mediated by FcγRIII⁺ phagocytes

Setiady¹,

Coccia²,

Park³

2010

Eur J Immunol

193

180

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Depletion of CD4 1 CD25 1 FoxP3 1 Treg using PC61 mAb (anti-murine CD25 rat IgG1) is widely used to characterize Treg function in vivo. However, the mechanism of Treg depletion remains largely unknown. Herein, we report the PC61 mAb's mechanism of action. In peripheral blood, a single injection of PC61 mAb eliminated $70% of CD4 1 FoxP3 1 cells with the remaining Treg expressing low or no CD25. Functional blockade of Fcc receptors with 2.4G2 mAb significantly inhibited PC61 mAb activity. Furthermore, Fcc receptor (FccR)III À/À mice were resistant to Treg depletion. FccRIII is expressed on immune cells including NK cells and macrophages that are the major effector cells for Ab-dependentcellular-cytotoxicity and Ab-dependent-cellular-phagocytosis, respectively. Depletion of NK cells had no effect, whereas depletion of phagocytes, including macrophages, by clodronate liposome significantly inhibited Treg depletion. Furthermore, in vitro, PC61 mAb can mediate Ab-dependent-cellular-phagocytosis of CD25 1 cells by WT or FccRIIB À/À , but not FccRIII À/À , macrophages. Altogether these data demonstrate the critical role of FccRIII 1 phagocytes in mediating Treg depletion by PC61 mAb. This finding may be useful in guiding the development of human Treg targeting therapy.Key words: CD25 . Fcc receptor . PC61 Ab . Phagocytes . Treg Supporting Information available online IntroductionNaturally occurring Treg play a critical role in the maintenance of peripheral tolerance. They can suppress not only CD4 1 and CD8 1 T cells, but also NK cells, macrophages and dendritic cells [1]. Treg are marked by expression of FoxP3 1 transcription factor (Foxp3), which confers the Treg's regulatory activity. Induction of Foxp3 expression in naïve T cells can convert them into Treg [2,3]. Before the discovery of Foxp3, Treg were identified by expression of CD25, an IL-2 receptor a subunit. Initially, CD25 was simply considered a Treg marker that was not associated with Treg function because of its expression on activated T cells without suppressive activity. More recently, however, it became clear that CD25, thus also IL-2, is essential for the generation, peripheral expansion and maintenance of Treg. CD25-deficient mice and mice lacking IL-2 or Foxp3 have a reduced Treg number and spontaneously develop a fatal lymphoproliferative autoimmune syndrome that can be rescued by adoptive transfer of Treg from WT mice [1]. Temporary neutralization of IL-2 using anti-IL-2 mAb also reduces Treg number, induces autoimmune gastritis in BALB/c mice and accelerates autoimmune diabetes in NOD mice [4]. Additionally, ectopic expression of IL-2 receptor b in the thymus increases Treg production [5]. A recent study using transgenic mice expressing GFP-linked Foxp3 shows that the peripheral expansion of CD25 À Treg is significantly reduced compared with that of CD25 Results and discussion Treg depletion by PC61 mAbWe first tested the extent of Treg depletion after CD25 mAb injection in C57BL/6 mice. In naïve mice (Fig. 1A left panel), around 70% of CD4 1 Fo...

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“…1). M2 cells were shown to induce differentiation of regulatory T cells [26]; conversely, regulatory T cells have been reported to induce alternative activation of human mononuclear phagocytes [27]. While general properties are retained from mouse to man, there are significant differences, such as the association of YM1, Fizz1 and Arginase 1 with M2 polarization in the mouse but not in man [18].…”

Section: Activation and Adaptive Responses Of Macrophagesmentioning

confidence: 99%

From phagocyte diversity and activation to probiotics: Back to Metchnikoff

Mantovani

2008

Eur J Immunol

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In this issue of the European Journal of Immunology, Siamon Gordon gives a detailed account of Metchnikoff's life and his achievements (Eur. J. Immunol. 2008. 38: 3257-3264). Looking back at the roots of innate immunity stimulates reflections on open issues in the field. Here, I give a personal view of some of these issues, including myeloid-derived suppressor cells, macrophage polarization and adaptive responses of mononuclear phagocytes. Key words: Macrophage activation Á Macrophages Á M1/M2 polarization Á Probiotics See accompanying article by Gordon IntroductionIn his scholarly review [1], Siamon Gordon tracks the roots of innate immunity to Elie Metchnikoff. The essay provides a fascinating insight into Metchnikoff's scientific life and how he tackled fundamental issues in science, some of which remain with us to this day. The perspective offered by a major player in the very same field of phagocytes and innate immunity [2,3] adds flavour and fascination to this article not necessarily present in other accounts [4]. Such a reflection on a central part of modern immunology stimulates consideration of remaining open issues and there follows a personal view of some of these.Phagocyte heterogeneity: From microphage-macrophage dichotomy to myeloid-derived suppressor cellsThe fundamental distinction between polymorphonuclear leukocytes (microphages) and mononuclear phagocytes (macrophages) was a major first step in the dissection of phagocyte heterogeneity and lineage differentiation. The identification of myeloid-derived suppressor cells (MDSC) [5][6][7] raises the questions whether the classic sharp distinction between the myeloid and the monocyte-macrophage differentiation and activation pathways is appropriate. In contrast to long-held views, neutrophils express specific transcriptional programmes in response to environmental signals [8]. MDSC include immature myeloid precursors that can further differentiate, and play a key role in the suppression of adaptive immunity in diverse pathological conditions ranging from cancer to chronic infections [5][6][7]. Are we dealing with a blurring of a classic distinction or with a well-defined third phagocyte population? Using current identification and separation criteria (e.g. Gr1, CD11b, F4/80) MDSC in the blood and lymphoid organs are a mixed population, which includes myeloid cells at different stages of differentiation and mononuclear phagocytes. Thus, the definition of MDSC remains an operational one rather than that of a cell type, a reality that is frequently neglected. The issue of lineage of the actual effectors of MDSC-mediated suppression is even more relevant when their recruitment and activation in non-lymphoid tissues is considered. For instance, do MDSC retain an immature phenotype in tumour tissues or do they differentiate into tumourassociated macrophages [9][10][11] [9,12,16,17], bacterial [43][44][45][46][47][48][49] and parasitic [50][51][52][53] infections. Evidence has also accumulated that polarized macrophages are more than mere spectators of i...

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CD4⁺CD25⁺Foxp3⁺regulatory T cells induce alternative activation of human monocytes/macrophages

Cited by 733 publications

References 37 publications

Mechanisms of sepsis‐induced immunosuppression and immunological modification therapies for sepsis

Mechanisms of sepsis‐induced immunosuppression and immunological modification therapies for sepsis

In vivo depletion of CD4⁺FOXP3⁺ Treg cells by the PC61 anti‐CD25 monoclonal antibody is mediated by FcγRIII⁺ phagocytes

From phagocyte diversity and activation to probiotics: Back to Metchnikoff

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CD4+CD25+Foxp3+regulatory T cells induce alternative activation of human monocytes/macrophages

Cited by 733 publications

References 37 publications

Mechanisms of sepsis‐induced immunosuppression and immunological modification therapies for sepsis

Mechanisms of sepsis‐induced immunosuppression and immunological modification therapies for sepsis

In vivo depletion of CD4+FOXP3+ Treg cells by the PC61 anti‐CD25 monoclonal antibody is mediated by FcγRIII+ phagocytes

From phagocyte diversity and activation to probiotics: Back to Metchnikoff

Contact Info

Product

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CD4⁺CD25⁺Foxp3⁺regulatory T cells induce alternative activation of human monocytes/macrophages

In vivo depletion of CD4⁺FOXP3⁺ Treg cells by the PC61 anti‐CD25 monoclonal antibody is mediated by FcγRIII⁺ phagocytes