Cutting Edge: Direct Suppression of B Cells by CD4+CD25+ Regulatory T Cells

Lim, Hyung W.; Hillsamer, Peter; Banham, Alison H.; Kim, Chang H.

doi:10.4049/jimmunol.175.7.4180

Cited by 517 publications

(444 citation statements)

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“…37 Lim et al also recently demonstrated that regulatory T cells can suppress B-celldependent immunoglobulin production and class switch recombination in the absence of T-helper cells. 38 However, the mechanism for the suppression remains unclear in these studies. We examined the direct effect of CD4 ϩ CD25 ϩ T cells on B cells and found that, when restimulated with either anti-CD3 or antigen, preactivated CD4 ϩ CD25 ϩ T cells mediated apoptosis of activated B cells by a cytotoxic granule-mediated mechanism.…”

Section: Discussionmentioning

confidence: 98%

Activated CD4+CD25+ T cells selectively kill B lymphocytes

Zhao

Thornton

DiPaolo

et al. 2006

Blood

430

337

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IntroductionCD4 ϩ CD25 ϩ regulatory/suppressor T cells were originally identified by their capacity to primarily control immune responses to autoantigens, 1-3 but recent studies have shown that they exert pleiotropic suppressive effects on immune responses to alloantigens, 4 tumor antigens, 5 and infectious agents. 6,7 The functional phenotype of CD4 ϩ CD25 ϩ T cells has been extensively characterized in vitro. CD4 ϩ CD25 ϩ T cells do not proliferate when stimulated via the TCR but are able to proliferate when costimulated with IL-2. 8,9 On activation via their TCR, they suppress the proliferation of both CD4 ϩ T cells 8 and CD8 ϩ T cells 10 by inhibiting the transcription of IL-2 mRNA. 8 In vitro studies have demonstrated that the suppression is mediated exclusively by a cell-contact-dependent, cytokine-independent mechanism. 4,9,10 However, suppression in some in vivo experimental models requires the cooperation of suppressive cytokines. [11][12][13] The nature of the target cells for CD4 ϩ CD25 ϩ T-cell-mediated suppression remains controversial. CD4 ϩ CD25 ϩ T cells can suppress the activation of CD8 ϩ T cells in the absence of professional antigenpresenting cells (APCs), 10 but this does not exclude the possibility that they are also capable of acting on other cell types. One recent study has suggested that some (or all) of the suppressive effects of mouse CD4 ϩ CD25 ϩ T cells on T-cell proliferation are secondary to CD4 ϩ CD25 ϩ T-cell-mediated killing of the responder cells by a perforin-independent, granzyme-B-dependent pathway. 14 In the day 3 thymectomy model of organ-specific autoimmune disease, CD4 ϩ CD25 ϩ T cells suppressed the activation of autoantigenspecific T cells and inhibited the production of autoantibodies to the target organ. 2,3 Similar results have been obtained in cell transfer studies using TCR transgenic T cells. [15][16][17][18] However, it remains unclear whether these results are secondary to a direct effect of CD4 ϩ CD25 ϩ T cells on B-cell function or whether the effects are mediated indirectly by an inhibition of T-helper function. One recent study has shown that activation of both human T regulatory 1 (Tr1)-like cells and CD4 ϩ CD25 ϩ T cells by cross-linking CD3 and CD46 induces potent lytic activity against T cells, monocytes, and dendritic cells. 19 In this study, we examined the effects of CD4 ϩ CD25 ϩ T cells on B-cell function. We demonstrate that CD4 ϩ CD25 ϩ T cells suppress B-cell proliferation in response to polyclonal B-cell activators by inducing death of the responding B cells. Most interestingly, B-cell death is not mediated by the Fas-Fas ligand (FasL) pathway, but instead is mediated by a granzyme-dependent, partially perforin-dependent pathway. The implications of these findings for the role of CD4 ϩ CD25 ϩ T cells in the control of B-cell function in vivo are discussed. Materials and methods MiceFemale BALB/c and C57BL/6 mice were obtained from the National Cancer Institute (Frederick, MD). Mice expressing a transgenic TCR specific for influenza hemagglutinin...

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Section: Discussionmentioning

confidence: 98%

Activated CD4+CD25+ T cells selectively kill B lymphocytes

Zhao

Thornton

DiPaolo

et al. 2006

Blood

430

337

View full text Add to dashboard Cite

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“…Decreased number and function of FOXP3 + Treg have also been described in the plasma cell-derived malignancy multiple myeloma [37] and in Sezary syndrome, the aggressive leukaemic variant of cutaneous T cell lymphoma [27,38]. Since Treg can suppress B as well as T cell function [39,40], the expansion of such tumours may be slowed by Treg. Therefore, immunotherapeutic strategies aiming to reduce Treg numbers, to improve the efficacy of cancer vaccines in haematological malignancies, may need to carefully balance advantages gained by improving T cell responses to tumour antigens with possible disadvantages arising from removing direct Treg suppression of the malignant population.…”

Section: Manipulation Of Treg For Cancer Therapymentioning

confidence: 99%

FOXP3⁺ regulatory T cells: Current controversies and future perspectives

2006

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Regulatory T cells (Treg) provide protection from autoimmune disease, graft‐versus‐host disease, transplant rejection and overwhelming tissue destruction during infections. Conversely, high Treg numbers enable cancer cells to evade the host immune response. Thus, Treg are seen as an important tool to manipulate the immune response. However, as the immunological community is trying to move this knowledge from mice to humans, contradictory results regarding the number and function of Treg in various diseases are appearing. This problem arises because we cannot clearly define Treg populations on the basis of expression of CD25 and other cell surface markers in humans. This review addresses the utility of the FOXP3 forkhead transcription factor for the identification of Treg populations and summarizes recent data on the expression of FOXP3 in lymphomas. It is crucial to really understand Treg biology before attempting therapies, including (i) the injection of expanded Treg to cure autoimmune disease or prevent graft‐versus‐host disease or (ii) the depletion or inhibition of Treg in cancer therapy. For instance, new data arising from the study of haematological malignancies highlight the additional complexity of systems where malignant cell populations may also be direct Treg targets.

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“…CD4 1 CD25 1 ab T cells are well known for their ability to control the activity of several immune cell populations in vitro and in vivo, including effector CD4 1 CD25 À and CD8 1 ab T cells [13], NK [14] and NKT cells [15], B cells [16], DC [17], and monocytes/macrophages [18]. As a result, CD4 1 CD25 1 ab T cells, and particularly those that develop in the thymus through a Foxp3-dependent genetic program [19,20], so-called ''naturally occurring'' Treg (nTreg), are pivotal to maintaining immune homeostasis and preventing inflammatory and autoimmune diseases [21].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

et al. 2009

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cd T cells are highly cytolytic lymphocytes that produce large amounts of pro-inflammatory cytokines during immune responses to multiple pathogens. Furthermore, their ability to kill tumor cells has fueled the development of cd-T-cell-based cancer therapies. Thus, the regulation of cd-T-cell activity is of great biological and clinical relevance. Here, we show that murine CD4 1 CD25 1 ab T cells, the vast majority of which express the Treg marker, Foxp3, abolish key effector functions of cd T cells, namely the production of the pro-inflammatory cytokines, IFN-c and IL-17, cytotoxicity, and lymphocyte proliferation in vitro and in vivo. We further show that suppression is dependent on cellular contact between Treg and cd T cells, results in the induction of an anergic state in cd lymphocytes, and can be partially reversed by manipulating glucocorticoid-induced TNF receptor-related protein (GITR) signals. Our data collectively dissect a novel mechanism by which the expansion and pro-inflammatory functions of cd T cells are regulated. IntroductionThe integration of multiple effector and regulatory mechanisms dictates the course of immune responses to self and non-self antigens. gd T cells are innate-like lymphocytes known to mount robust responses to infectious pathogens [1] and tumors [2], while also regulating tissue homeostasis and repair [3]. Importantly, several of these functions are non-redundant, as demonstrated by the immunopathology phenotypes of TCR-d-deficient mice [4]. It is also well documented that upon pathogen challenge (for example, with Plasmodium falciparum, Mycobacterium tuberculosis, Haemophilus influenzae, or Streptococcus pneumoniae), gd T cells are one of the immune populations that expands most dramatically in human peripheral blood [1,5,6].In contrast with adaptive ab T cells, activated gd lymphocytes are capable of ''immediate'' cytotoxicity and cytokine secretion [5]. In fact, we have recently shown that murine gd T cells become functionally competent in the thymus, particularly regarding the production of pro-inflammatory cytokines . Furthermore, several reports have demonstrated the crucial contributions of gd T cells to the reservoirs of such cytokines in the context of anti-tumor immunity [8], immune responses to infection [9], and autoimmunity [9,10]. While these data highlight the importance of understanding how the [17], and monocytes/macrophages [18]. As a result, CD4 1 CD25 1 ab T cells, and particularly those that develop in the thymus through a Foxp3-dependent genetic program [19,20], so-called ''naturally occurring '' Treg (nTreg), are pivotal to maintaining immune homeostasis and preventing inflammatory and autoimmune diseases [21]. On the other hand, Treg-suppressive functions are also known to diminish immunity to pathogens and to tumors [22,23]. Provocatively, an inverse correlation between circulating human Treg frequencies and gd-T-cell numbers in cancer patients has been recently reported [24].Building on these foundations, we show here that Treg suppress gd-T-cell ...

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Cutting Edge: Direct Suppression of B Cells by CD4+CD25+ Regulatory T Cells

Cited by 517 publications

References 24 publications

Activated CD4+CD25+ T cells selectively kill B lymphocytes

Activated CD4+CD25+ T cells selectively kill B lymphocytes

FOXP3⁺ regulatory T cells: Current controversies and future perspectives

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

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Cutting Edge: Direct Suppression of B Cells by CD4+CD25+ Regulatory T Cells

Cited by 517 publications

References 24 publications

Activated CD4+CD25+ T cells selectively kill B lymphocytes

Activated CD4+CD25+ T cells selectively kill B lymphocytes

FOXP3+ regulatory T cells: Current controversies and future perspectives

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

Contact Info

Product

Resources

About

FOXP3⁺ regulatory T cells: Current controversies and future perspectives