Induction of Peripheral T Cell Tolerance by Antigen-Presenting B Cells. I. Relevance of Antigen Presentation Persistence

Raimondi, Giorgio; Zanoni, Ivan; Citterio, Stefania; Ricciardi‐Castagnoli, Paola; Granucci, Francesca

doi:10.4049/jimmunol.176.7.4012

Cited by 24 publications

(24 citation statements)

References 34 publications

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“…Several lines of evidence support the notion that other cell types, such as mast cells, 51 macrophages, 52,53 plasmacytoid DCs, [54][55][56] and B cells 57,58 may also be involved in T-cell tolerance. Blockade of the SCF/ckit pathway may influence the number and functional activity of these cells.…”

Section: Discussionmentioning

confidence: 79%

Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function

Pan

Wang²,

Yin³

et al. 2008

Blood

289

224

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IntroductionImmune-based therapy has achieved a certain level of success; however, the overall therapeutic effect has been much less promising due to the immune suppressive mechanisms associated with advanced malignancies. 1 To achieve a better therapeutic efficacy of immune activation therapy, the mechanism or mechanisms by which a large tumor burden prevents immune activation from inducing effective antitumor immunity needs to be elucidated.Tumor growth is accompanied by an increase in the number of Gr-1 ϩ Mac-1 ϩ myeloid-derived suppressor cells (MDSCs) 2-4 and tumor-specific T regulatory cells (Tregs) 5,6 with strong immune suppressive activity in cancer patients and in tumor-bearing mice. [7][8][9] Both MDSCs and Tregs may be directly involved in immune unresponsiveness in active immune therapy.It has been demonstrated that MDSCs are involved in T-cell hyporesponsiveness in tumor-bearing mice. Several mechanisms by which MDSCs regulate the tumor-specific T-cell response have recently been proposed and the in vivo immune regulatory effects of MDSCs on tumor-specific T-cell response have been identified. 7-12 T-cell inactivation can be mediated by MDSCs through IFN␥-dependent nitric oxide (NO) production [12][13][14][15][16] or the Th2-mediated IL-4/IL-13-dependent arginase 1 pathway. 14,[17][18][19][20][21][22] In addition, a mechanism of ROS-mediated cell killing has been proposed. 3,23,24 Furthermore, MDSCs can inhibit cytotoxic T lymphocyte (CTL) responses through NOdependent or -independent mechanisms. Cell-to-cell contact appeared to be crucial in these mechanisms. 25 Our laboratory has further identified a novel mechanism of MDSC-mediated immune suppression on activated T cells through the development of Foxp3 ϩ T regulatory cells (Tregs) and T-cell tolerance both in vitro and in tumor-bearing mice. The induction of Tregs by MDSCs requires IFN-␥ and IL-10 but is independent of the NO-mediated suppressive mechanism. 11 To overcome MDSCmediated immune suppression and prevent Treg induction, it is critical to identify the tumor factors that are required for MDSC accumulation in tumor-bearing animals.Several lines of evidence support the hypothesis that the development and expansion of MDSCs may be modulated by tumor-secreted factors. MDSCs in tumor-bearing animals can differentiate into mature dendritic cells or remain as MDSCs with inhibitory activities, depending on the local cytokine milieu. 26,27 Human renal cell carcinoma cell lines release soluble factors (IL-6, M-CSF) that inhibit the differentiation of CD34 ϩ cells into dendritic cells (DCs) and trigger their commitment toward monocytic cells. 28 In a transgenic mammary tumor, VEGF levels correlate with the MDSC number. 29 Moreover, the in vivo infusion of vascular endothelial growth factor (VEGF) can induce MDSC development in naive mice and impair DC function and differentiation. 30 Granulocyte macrophage-colony-stimulating factor (GM-CSF) secretion has correlated with the capacity of tumor metastases and the GM-CSF and IL-3 in conditioned mediu...

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Section: Discussionmentioning

confidence: 79%

Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function

Pan

Wang²,

Yin³

et al. 2008

Blood

289

224

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“…More recently, the role of B cells as APC has been revisited. Antigen presentation by B cells has been shown to induce tolerance [24,31], and resting B cells are known to play essential roles in transplantation tolerance and tolerance against tumors in a MHC-class II dependent manner [32][33][34]. Unlike DC, B cells are APC that do not constitutively express high levels of co-stimulatory molecules like MHC class II and B7 [35].…”

Section: Discussionmentioning

confidence: 99%

Resting B cells expand a CD4⁺CD25⁺Foxp3⁺ Treg population via TGF‐β3

Shah

Qiao

2008

Eur J Immunol

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Regulatory T cells (Treg) play critical roles in maintaining tolerance and preventing autoimmunity. It is not fully clear how these cells are generated and maintained. Here, we show that resting B cells are able to expand Treg. This expansion requires TGF-b3 and signaling through the TCR and CD28. Upon activation, B cells express less TGF-b3, which reduces their capacity to expand Treg and which also results in increased Treg death. This may ensure that B cells can function as potent professional antigen presenting cells during infections. However, in the absence of any infection, we find that B-cell-deficient lMT mice have decreased percentages of Treg in the periphery. Our data suggest that resting B cells, which may be presenting self-antigens to T cells, can expand and maintain specific Treg and thus might be involved in the prevention of autoimmunity. Key words: B cells . Regulatory T cells . Tolerance Supporting Information available online IntroductionRegulatory T cells (Treg) are a subset of T cells that can actively suppress innate as well as adaptive immunity and have been implicated in self-tolerance, autoimmunity, cancer, transplantation immunology and a myriad of infectious diseases [1][2][3][4][5][6]. There are numerous different subsets of Treg based on their phenotypic markers, amonge which the naturally occurring Treg (nTreg) population is well studied and characterized. nTreg are a subset of CD4 1 T cells expressing CD25 and the transcription factor Forkhead box protein 3 (Foxp3). Foxp3 has been shown to be the master regulator for the generation of nTreg. Although Foxp3 À/À mice lack CD4 1 CD25 1 T cells, expression of Foxp3 in CD4 1 CD25 -T cells is sufficient for converting them into CD4 1 CD25 1 T cells with suppressive function [7,8].CD4 1 CD25 1 Foxp3 1 Treg arise in the thymus and enter into the periphery where they constitute $5-10% of the CD4 1 T cells. nTreg generation in the thymus is thought to require high-affinity peptide-MHC class II interactions in contrast to low-affinity peptide-MHC class II interactions required for positive selection of conventional CD4 1 T cells [9,10]. There are also strong evidences for the generation of CD4 1 CD25 1 Foxp3 1 Treg in the periphery. Experiments carried out in thymectomized or RAG-2-deficient mice lacking CD4 1 CD25 1 T cells show that nTreg can be generated in the periphery from CD4 1 CD25 À T cells [11,12].In addition to co-stimulation via the B7-CD28 and TCR-MHC class II pathways, various cytokines such as IL-2, TGF-b1 and IL-10 have been associated with the generation of peripheral Treg. IL-2 and IL-2R knockout mice have few, if any, nTreg and develop severe lymphoproliferation and autoimmunity [13,14]. TGF-b1 or IL-10 have been shown to expand Treg and even convert CD4 1 CD25 À T cells into CD4 1 CD25 1 T cells with suppressive functions [13,[15][16][17][18].Antigen presenting cells (APC) express both MHC class II as well as B7 molecules and secrete cytokines that may modulate the differentiation of T cells into either T-effector or T-r...

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“…18 DC-tg mice were backcrossed on the BALB/c Rag2-deficient background for at least 10 generations. BALB/c and congenic CB-17 mice (expressing the IgG2a b ) were obtained from Harlan Italy, and DEREG mice on the BALB/c background were obtained from T. Sparwasser (Twincore, Hannover, Germany).…”

Section: Micementioning

confidence: 99%

Migratory, and not lymphoid-resident, dendritic cells maintain peripheral self-tolerance and prevent autoimmunity via induction of iTreg cells

Vitali¹,

Mingozzi²,

Broggi³

et al. 2012

Blood

Self Cite

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IntroductionInduction and maintenance of T-cell tolerance toward self-antigens is vital to prevent autoimmunity. To this purpose, many different overlapping and nonoverlapping mechanisms of T-cell tolerization exist, both at central and peripheral levels. [1][2][3][4][5] A common vision of how dendritic cells (DCs) contribute to the induction and maintenance of peripheral CD4 ϩ T-cell tolerance is that, in resting conditions, immature DCs, expressing low levels of signal 1 (specificity) and low or no levels of signal 2 (costimulation), are able to induce T-cell unresponsiveness.However, the effective knowledge concerning the contribution of DCs in inducing and maintaining CD4 ϩ T-cell tolerance in peripheral lymphoid organs derives from the selective analysis of specific DC subpopulations. In particular, CD205 ϩ DCs are able to induce CD4 ϩ T-cell tolerance in conditions of suboptimal activation. [6][7][8][9] Moreover, steady-state migratory DC (ssmDC) subpopulations from the gut and the skin, phenotypically CD103 ϩ and CD103 Ϫ , respectively, mediate the conversion of naive T cells into Foxp3 ϩ regulatory T cells (iTreg) in a retinoic acid (RA)-dependent manner. [10][11][12][13] Because the lymph constantly carries peptides for loading on both migratory and lymphoid tissue resident immature DCs in a dose range suitable for tolerization, 14 it cannot be excluded that, in addition to the analyzed populations and in agreement with the common vision, all conventional immature DCs can induce autoantigen specific CD4 ϩ T-cell tolerance in the periphery. Therefore, it was relevant to know whether DCs in general are able to induce T-cell tolerance at the steady state or whether this is a prerogative of specialized subsets. We investigated this question using an experimental system where antigen presentation, in contrast to previous studies, is not a priori confined to a specific DC subpopulation but is extended to all conventional DC subtypes. Specifically, we adopted the 2a T transgenic animal model. 15 In this experimental system, T-cell receptor (TCR) transgenic T cells (2a T cells) recognize a portion of the CH3 region (435-451) of the IgG2a b , the Bpep, in association with the MHC molecule, I-A d . We also generated a mouse model in which the Bpep was presented by CD11c ϩ cells that include all conventional DC subtypes. By performing a systematic study of the behavior of naive autoantigen-specific T cells after interaction with all conventional CD11c ϩ DCs in homeostatic conditions, we found that DCs are able to induce CD4 ϩ T-cell tolerance by promoting the conversion of autoantigen-specific naive T cells into iTreg cells. Among the different DC subtypes, ssmDCs possess the unique ability to induce antigen-specific iTreg cells in an RA-dependent manner. Diversely, lymphoid tissue resident DCs do not show this capacity. Therefore, iTreg cells develop solely in lymph nodes and not in the spleen, which does not host the migratory DC subtype. We also show that iTreg cells that are newly generated in lymph nodes do n...

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Induction of Peripheral T Cell Tolerance by Antigen-Presenting B Cells. I. Relevance of Antigen Presentation Persistence

Cited by 24 publications

References 34 publications

Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function

Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function

Resting B cells expand a CD4⁺CD25⁺Foxp3⁺ Treg population via TGF‐β3

Migratory, and not lymphoid-resident, dendritic cells maintain peripheral self-tolerance and prevent autoimmunity via induction of iTreg cells

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Induction of Peripheral T Cell Tolerance by Antigen-Presenting B Cells. I. Relevance of Antigen Presentation Persistence

Cited by 24 publications

References 34 publications

Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function

Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function

Resting B cells expand a CD4+CD25+Foxp3+ Treg population via TGF‐β3

Migratory, and not lymphoid-resident, dendritic cells maintain peripheral self-tolerance and prevent autoimmunity via induction of iTreg cells

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Resting B cells expand a CD4⁺CD25⁺Foxp3⁺ Treg population via TGF‐β3