Altered B Cell Development and Anergy in the Absence of <i>Foxp3</i>

Leonardo, Steven; Josephson, Jennifer; Hartog, Nicholas; Gauld, Stephen B.

doi:10.4049/jimmunol.1000136

Cited by 37 publications

(62 citation statements)

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“…Studies by Kim et al [20] established that Treg cells play a vital role throughout the lifespan of the host. We have previously shown, using a model devoid of Treg cells from birth, that Treg cells are essential to maintain B-cell anergy [3]. Here we show that the requirement …”

Section: Discussionmentioning

confidence: 56%

“…The absence of regulatory T (Treg) cells results in the development of IPEX, a fatal disease associated with the development of significant autoantibodies and autoimmunity [1,2]. The development of autoantibodies suggests that Treg cells play a key role in regulating B-cell tolerance, a statement supported by our previous study showing a role for Treg cells in the maintenance of B-cell anergy [3].Numerous signaling molecules have been identified whose absence prevents the establishment or maintenance of B-cell Correspondence: Dr. Stephen B. Gauld e-mail: sgauld@mcw.edu anergy at the intrinsic level (reviewed in [4]). However, our understanding of B-cell extrinsic mechanisms that regulate B-cell anergy remains poor.…”

mentioning

confidence: 51%

“…Possible explanations may include enhanced de novo synthesis of T FH cells by DCs and B cells, cell lineages important for the generation of T FH cells [13,25,26]. Indeed, DC-and B-cell populations exhibit significant dysregulation and activation in the absence of Treg cells [3,20] In summary, our data provide mechanistic insight into how the absence of Treg cells results in significant autoantibody production. We demonstrate that the absence of Treg cells results in the rapid expansion of T FH cells, and especially GC-T FH cells, which are sufficient to drive antibody production by anergic B cells.…”

Section: Discussionmentioning

confidence: 81%

“…Our previous studies have shown that the absence of Treg cells from birth results in a failure of B-cell anergy [3]. To determine whether the depletion of Treg cells in an adult host, where anergy was already established, resulted in a loss of B-cell anergy, we crossed the Ars/A1 model of B-cell anergy [22] with Foxp3 DTR mice.…”

Section: Loss Of B-cell Anergy Following Depletion Of Treg Cells In Amentioning

confidence: 99%

“…We previously reported the presence of a non-B-cell population expressing the germinal center marker GL7 in mice deficient of Treg cells from birth [3]. To examine if these cells were also present in adult mice depleted of Treg cells, we costained splenocytes from Foxp3 DTR mice treated with PBS or DT with antibodies specific for GL7 and CD4.…”

Section: Rapid Expansion Of Gl7 + T Cells In the Absence Of Treg Cellsmentioning

confidence: 99%

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Expansion of follicular helper T cells in the absence of Treg cells: Implications for loss of B‐cell anergy

et al. 2012

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The maintenance of B-cell anergy is essential to prevent the production of autoantibodies and autoimmunity. However, B-cell extrinsic mechanisms that regulate B-cell anergy remain poorly understood. We previously demonstrated that regulatory T (Treg) cells are necessary for the maintenance of B-cell anergy. We now show that in Treg-cell-deficient mice, helper T cells are necessary and sufficient for loss of B-cell tolerance/anergy. In addition, we show that the absence of Treg cells is associated with an increase in the proportion of CD4 + cells that express GL7 and correlated with an increase in germinal center follicular helper T (GC-T FH ) cells. These GC-T FH cells, but not those from Tregcell-sufficient hosts, were sufficient to drive antibody production by anergic B cells. We propose that a function of Treg cells is to prevent the expansion of T FH cells, especially GC-T FH cells, which support autoantibody production.Keywords: anergy r autoimmunity r B cells r T FH r Treg cells Supporting Information available online IntroductionThe production of autoantibodies due to loss of B-cell tolerance is central to the development of autoimmunity. Our understanding of the mechanisms that maintain B-cell tolerance, especially B-cell anergy, remains poorly defined. The absence of regulatory T (Treg) cells results in the development of IPEX, a fatal disease associated with the development of significant autoantibodies and autoimmunity [1,2]. The development of autoantibodies suggests that Treg cells play a key role in regulating B-cell tolerance, a statement supported by our previous study showing a role for Treg cells in the maintenance of B-cell anergy [3].Numerous signaling molecules have been identified whose absence prevents the establishment or maintenance of B-cell Correspondence: Dr. Stephen B. Gauld e-mail: sgauld@mcw.edu anergy at the intrinsic level (reviewed in [4]). However, our understanding of B-cell extrinsic mechanisms that regulate B-cell anergy remains poor. DCs have been shown to both positively and negatively regulate autoantibody production [5][6][7]. Helper T cells, or signals associated with T-cell help, appear to negatively regulate B-cell tolerance [8][9][10][11][12]. It remains unclear as to which helper T-cell populations can support autoantibody production.Follicular helper T (T FH ) cells are defined based on their expression of the chemokine receptor CXCR5, the transcription factor Bcl6, and play an essential role in providing help to B cells, promoting antibody production [13][14][15]. However, a role for T FH cells in the production of autoantibodies is less well defined. The expansion of T FH cells is known to be associated with a lupus-like disease in sanroque mice and CD4 + cells from the sanroque model support antichromatin autoantibody production in an adoptive transfer system [16,17]. A study by Simpson et al. [18] In our study, we use the Foxp3 DTR mouse model [20] to deplete the complete Treg-cell population in adult hosts and show that Treg cells are essential to prevent th...

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Section: Discussionmentioning

confidence: 56%

mentioning

confidence: 51%

Section: Discussionmentioning

confidence: 81%

Section: Loss Of B-cell Anergy Following Depletion Of Treg Cells In Amentioning

confidence: 99%

Section: Rapid Expansion Of Gl7 + T Cells In the Absence Of Treg Cellsmentioning

confidence: 99%

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Expansion of follicular helper T cells in the absence of Treg cells: Implications for loss of B‐cell anergy

et al. 2012

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Foxp3⁺ regulatory T cells ensure B lymphopoiesis by inhibiting the granulopoietic activity of effector T cells in mouse bone marrow

et al. 2014

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Foxp3 + Treg cells are crucial for maintaining T-cell homeostasis, but their role in B-cell homeostasis remains unclear. Here, we found that Foxp3 mutant scurfy mice had fewer B-lineage cells and progenitors, including common lymphoid progenitors and lymphoidprimed multipotent progenitors, but higher myeloid-lineage cell numbers in BM compared with WT littermates. Homeostasis within the HSC compartment was also compromised with apparent expansion of long-and short-term HSCs. This abnormality was due to the lack of Treg cells, but not to the Treg-cell extrinsic functions of Foxp3 or cellautonomous defects. Among cytokines enriched in the BM of scurfy mice, IFN-γ affected only B lymphopoiesis, but GM-CSF, TNF, and IL-6 collectively promoted granulopoiesis at the expense of B lymphopoiesis. Neutralization of these three cytokines reversed the hematopoietic defects on early B-cell progenitors in scurfy mice. Treg cells ensured B lymphopoiesis by reducing the production of these cytokines by effector T cells, but not by directly affecting B lymphopoiesis. These results suggest that Treg cells occupy an important niche in the BM to protect B-lineage progenitor cells from excessive exposure to a lymphopoiesis-regulating milieu.Keywords: B lymphopoiesis r Foxp3 r Granulopoietins r Hematopoiesis r Regulatory T cells Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction CD4 + Foxp3 + Treg cells are essential for maintaining immune homeostasis, as evidenced by the severe autoimmune lymphoproliferative disease observed in Treg-cell-deficient mice and humans [1,2]. Treg cells were initially identified in the secondary lymphoid tissues where they suppress the initial priming and Correspondence: Prof. Jeehee Youn e-mail: jhyoun@hanyang.ac.kr effector differentiation of autoreactive T cells [3]. They function by directly suppressing T cells and/or interacting with DCs to limit their ability to prime T cells effectively [4,5]. In addition to their constitutive presence in secondary lymphoid tissues, Treg cells have been found in several nonlymphoid sites, such as mucosal tissue, skin, liver, and lung, during inflammation as well as in steady-state conditions [6][7][8][9][10]. These Treg cells appear to regulate * These authors contributed equally to this work. * * These senior authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 168Sunghoon Kim et al. Eur. J. Immunol. 2015. 45: 167-179 tissue-tropic autoimmunity and inflammation, and alter pathogen clearance during peripheral infection. A diverse array of adhesion molecules and chemokine receptors that are expressed on Treg cells seem to license them to migrate to peripheral tissues. A fraction of Treg cells have been shown to express the BM homing receptor CXCR4 [11], suggesting the existence of a niche for Treg cells in the BM. Indeed, there are studies showing that healthy human BM contains a substantial number of Treg cells that traffic via CXC...

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Fatal autoimmunity results from the conditional deletion of Snai2 and Snai3

Pioli

Chen

Weis

et al. 2015

Cellular Immunology

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Transcriptional regulation of gene expression is a key component of orchestrating proper immune cell development and function. One strategy for maintaining these transcriptional programs has been the evolution of transcription factor families with members possessing overlapping functions. Using the germ line deletion of Snai2 combined with the hematopoietic specific deletion of Snai3, we report that these factors function redundantly to preserve the development of B and T cells. Such animals display severe lymphopenia, alopecia and dermatitis as well as profound autoimmunity manifested by the production of high levels of autoantibodies as early as 3 weeks of age and die by 30 days after birth. Autoantibodies included both IgM and IgG isotypes and were reactive against cytoplasmic and membranous components. A regulatory T cell defect contributed to the autoimmune response in that adoptive transfer of wild type regulatory T cells alleviated symptoms of autoimmunity. Additionally, transplantation of Snai2/Snai3 double deficient bone marrow into Snai2 sufficient Rag2−/− recipients resulted in autoantibody generation. The results demonstrated that appropriate expression of Snai2 and Snai3 in cells of hematopoietic derivation plays an important role in development and maintenance of immune tolerance.

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Altered B Cell Development and Anergy in the Absence of Foxp3

Abstract: Material Supplementary 6.DC1http://www.jimmunol.org/content/suppl/2010/07/16/jimmunol.100013

Cited by 37 publications

References 41 publications

Expansion of follicular helper T cells in the absence of Treg cells: Implications for loss of B‐cell anergy

Expansion of follicular helper T cells in the absence of Treg cells: Implications for loss of B‐cell anergy

Foxp3⁺ regulatory T cells ensure B lymphopoiesis by inhibiting the granulopoietic activity of effector T cells in mouse bone marrow

Fatal autoimmunity results from the conditional deletion of Snai2 and Snai3

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Altered B Cell Development and Anergy in the Absence of Foxp3

Abstract: Material Supplementary 6.DC1http://www.jimmunol.org/content/suppl/2010/07/16/jimmunol.100013

Cited by 37 publications

References 41 publications

Expansion of follicular helper T cells in the absence of Treg cells: Implications for loss of B‐cell anergy

Expansion of follicular helper T cells in the absence of Treg cells: Implications for loss of B‐cell anergy

Foxp3+ regulatory T cells ensure B lymphopoiesis by inhibiting the granulopoietic activity of effector T cells in mouse bone marrow

Fatal autoimmunity results from the conditional deletion of Snai2 and Snai3

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Foxp3⁺ regulatory T cells ensure B lymphopoiesis by inhibiting the granulopoietic activity of effector T cells in mouse bone marrow