Innate pro–B-cell progenitors protect against type 1 diabetes by regulating autoimmune effector T cells

Montandon, Ruddy; Korniotis, Sarantis; Layseca-Espinosa, Esther; Gras, Christophe; Mégret, Jérôme; Ezine, Sophie; Dy, Michel; Zavala, Flora

doi:10.1073/pnas.1222446110

Cited by 45 publications

(63 citation statements)

References 65 publications

(63 reference statements)

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“…Treatment of NOD mice at young ages with TLR2, TLR3, TLR4 and TLR9 ligands resulted in a considerable delay in T1D by activating both innate and adaptive immune responses (27, 28, 44-46). However, these ligands were not known to be effective in inducing protection from the disease at later stages.…”

Section: Discussionmentioning

confidence: 99%

Fungal β-Glucan, a Dectin-1 Ligand, Promotes Protection from Type 1 Diabetes by Inducing Regulatory Innate Immune Response

Karumuthil‐Melethil

Gudi

Johnson

et al. 2014

The Journal of Immunology

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Beta-glucans (β-glucans) are naturally occurring polysaccharides in cereal grains, mushrooms, algae, or microbes including bacteria, fungi, and yeast. Immune cells recognize these β-glucans through a cell surface pathogen recognition receptor (PRR) called Dectin-1. Studies using β-glucans and other Dectin-1 binding components have demonstrated the potential of these agents in activating the immune cells for cancer treatment and controlling infections. Here, we show that the β-glucan from Saccharomyces cerevisiae induces the expression of immune regulatory cytokines (IL-10, TGF-β1 and IL-2) and a tolerogenic enzyme (Indoleamine 2, 3-dioxygenase; IDO) in bone marrow derived DCs (BM DCs) as well as spleen cells. These properties can be exploited to modulate autoimmunity in non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). Treatment of pre-diabetic NOD mice with low dose β-glucan resulted in a profound delay in hyperglycemia and this protection was associated with increase in the frequencies of Foxp3-, LAP-, and GARP-positive T cells. Upon antigen presentation, β-glucan-exposed DCs induced a significant increase in Foxp3− and LAP− positive T cells in in vitro cultures. Further, systemic co-administration of β-glucan plus pancreatic β-cell-Ag resulted in an enhanced protection of NOD mice from T1D as compared to treatment with β-glucan alone. These observations demonstrate that the innate immune response induced by low dose β-glucan is regulatory in nature and can be exploited to modulate T cell response to β-cell-Ag for inducing an effective protection from T1D.

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Section: Discussionmentioning

confidence: 99%

Fungal β-Glucan, a Dectin-1 Ligand, Promotes Protection from Type 1 Diabetes by Inducing Regulatory Innate Immune Response

Karumuthil‐Melethil

Gudi

Johnson

et al. 2014

The Journal of Immunology

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“…In this study, we did not intend to fully characterize Bregs and RegMCs, but rather understand their signature, their contribution to alloresponses control and possible mechanisms of action. Indeed, following depletion of CD8 + Tregs, the development of such regulatory populations was associated with the emergence of cytotoxic antidonor immune responses, that correlated with described killer activity of Bregs and RegMCs (30,31), and with decreased cellular and humoral immune responses, particularly by guest on May 7, 2018 http://www.jimmunol.org/ evident for RegMCs. In addition, we described a strong induction of immunosuppressive molecules in the graft, such as IL-10 or even Foxp3, correlating also with described Bregs and RegMCs characteristics (11,29,42), and suggesting homing of new regulatory cells to the graft.…”

Section: Discussionmentioning

confidence: 99%

Compensatory Regulatory Networks between CD8 T, B, and Myeloid Cells in Organ Transplantation Tolerance

Bézie

Picarda

Ossart

et al. 2015

The Journal of Immunology

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In transplantation tolerance, numerous regulatory populations have the capacity to inhibit allograft rejection; however, their compensatory capacities have never been clearly evidenced. We have previously demonstrated that the tolerogenic effect mediated by CD8+CD45RClow regulatory T cells (Tregs) in a model of organ transplantation with CD40Ig could be abrogated by permanent depletion of CD8+ cells that resulted in allograft rejection in half of the recipients. This result demonstrated that CD8+ Tregs were essential, but also that half of the recipients still survived indefinitely. We also demonstrated that no other regulatory populations, besides CD8+ Tregs, could induce and maintain allograft tolerance in CD40Ig-treated tolerant animals. In the current study, we analyzed the mechanisms that arose following CD8+ Treg depletion and allowed establishment of networks of new regulatory cells to maintain allograft survival. We identified regulatory B cells (Bregs) and regulatory myeloid cells (RegMCs) as being responsible of the maintenance of the long-term allograft survival. We demonstrated that both regulatory cell subsets efficiently inhibited antidonor immune responses in adoptively transferred recipients. Although Bregs were induced, they were not essential for the maintenance of the graft as demonstrated in IgM-deficient recipients. In addition, we showed that RegMCs were the most suppressive and acted alone, whereas Bregs activity was associated with increased suppressive activity of other subsets in adoptively transferred recipients. Altogether, to our knowledge, we demonstrated in this study for the first time the emergence of both Bregs and RegMCs following Tregs depletion and highlighted the importance of regulatory cell networks and their synergistic potential in transplantation.

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“…For example, splenic marginal zone (MZ) (5–7), MZ-precursor (MZ-P) or Transitional 2 (T2) (8–11), follicular (FO) (7, 9, 12), CD1dhi CD5+ B cells (13), pro-B cells (14), and even plasma cells (15, 16) have been shown to exert regulatory activity. Nevertheless, IL-10+ cells still remain a minority of the B cells even within these enriched subsets (e.g.…”

Section: Phenotypic Identification Of Bregsmentioning

confidence: 99%

“…Whether the increase in IL-10+ B cells represents stochastic expression of IL-10 by activated B cells, or is due to in vitro maturation of Breg progenitors as has been suggested (2), remains unclear since there are no transcription factors or other markers that identify Bregs as a lineage. On the other hand, stimulation of bone marrow cells with TLR ligands in vitro can give rise to pro-B cells that can prevent onset of diabetes upon transfer into pre-diabetic NOD mice (14). These cells clearly develop into mature B cells after transfer, although it is unclear which subset/maturation state is responsible for the suppressive effect observed.…”

Section: Phenotypic Identification Of Bregsmentioning

confidence: 99%

“…In the presence of Bregs, DCs decrease their antigen presenting capacity and increase their production of IL-4 while decreasing their production of IL-12 (24). Finally, induction of Bregs by LPS stimulation results in FasL upregulation which may kill target cells and TGF-β upregulation which decreases antigen presentation by APCs and promotes Tregs (14, 27, 28). …”

Section: Mechanism Of Actionmentioning

confidence: 99%

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Role of B cells in tolerance induction

Kim

Rothstein

Markmann

2015

Current Opinion in Organ Transplantation

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Purpose B cells are known to play a central role in humoral immunity and to boost cellular immunity, however, in a variety of experimental models, B cell subsets ameliorate inflammation and autoimmune disease, indicating that they can also play a regulatory role. Here we highlight the advances in regulatory B cell (Breg) biology of the past year with an emphasis on findings pertinent to transplantation. Several recent observations highlight the relevance to clinical transplantation. Data from at least three independent groups demonstrated that spontaneously tolerant renal transplant recipients exhibit a peripheral blood B cell signature although the significance of these data remains unclear. Moreover, new data suggest that regulatory B cells may serve as a biomarker for long-term allograft outcomes. Finally, recent evidence suggesting that plasma cells may be an essential component of Bregs raises new concerns about targeting antibody producing cells. Recent findings We describe new information on Breg mechanisms of action to suppress the alloresponse, signals to expand Bregs in vitro, and more functional evidence of Breg involvement in operationally tolerant kidney patients and in maintaining stable allograft function. Summary While lymphocyte depletion remains central to tolerance induction therapy, the sparing or expansion of regulatory B cells may be an additional strategy to preempt graft rejection.

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Innate pro–B-cell progenitors protect against type 1 diabetes by regulating autoimmune effector T cells

Cited by 45 publications

References 65 publications

Fungal β-Glucan, a Dectin-1 Ligand, Promotes Protection from Type 1 Diabetes by Inducing Regulatory Innate Immune Response

Fungal β-Glucan, a Dectin-1 Ligand, Promotes Protection from Type 1 Diabetes by Inducing Regulatory Innate Immune Response

Compensatory Regulatory Networks between CD8 T, B, and Myeloid Cells in Organ Transplantation Tolerance

Role of B cells in tolerance induction

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