Dendritic cells in the thymus contribute to T-regulatory cell induction

Proietto, Anna I; Dommelen, Serani van; Zhou, Penghui; Rizzitelli, Alexandra; D’Amico, Angela; Steptoe, Raymond J.; Naik, Shalin H.; Lahoud, Mireille H.; Liu, Yang; Zheng, Pan; Shortman, Ken; Wu, Li

doi:10.1073/pnas.0810268105

Cited by 268 publications

(311 citation statements)

References 58 publications

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“…B cells could facilitate graft tolerance by inducing allograft-specific Tregs across an MHC barrier (57, 58), a mechanism that may be of significance in the context of graft-versus-host disease. Though the mechanism by which B cells could provide immunological tolerance to solid-organ grafts in the clinic are as yet unidentified, our data with BAFF-Tg mice suggests that B cells can accumulate within the thymus, where they can present cognate MHC-Ag complexes to engender thymic Tregs, mechanisms previously associated with DCs (5,41).…”

Section: Discussionmentioning

confidence: 86%

“…Intrathymic Treg cell selection requires cognate interactions with peptide-MHC II complexes on the surface of thymic APCs (4,41). We could show that resident thymic B cells express surface MHC II molecules, as well as the costimulatory molecules CD80 and CD86 (data not shown), indicating they have the required machinery for Treg selection.…”

Section: Thymic B Cells Provide Cognate Help For the Expansion Of Natmentioning

confidence: 87%

“…The thymus harbors a network of APCs including cortical TECs, mTECs, and DCs. Evidence indicates these cells could act coordinately to control T cell development, as deletion of MHC II from either B.M.-derived cells or thymic epithelial cells still allows Treg development (41,48,49). The question remains whether the diverse range of intrathymic APCs make individual and specific contributions to the development of Tregs with unique specificities (47).…”

Section: Discussionmentioning

confidence: 99%

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A Role for Intrathymic B Cells in the Generation of Natural Regulatory T Cells

Walters

Webster

Daley

et al. 2014

The Journal of Immunology

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B cells inhabit the normal human thymus, suggesting a role in T cell selection. In this study, we report that B cells can modulate thymic production of CD4+ Foxp3+ T cells (regulatory T cells [Tregs]). Mice with transgenic expression of BAFF (BAFF-Tg) harbor increased numbers of Helios+Foxp3+ thymic Tregs and, similar to some human autoimmune conditions, also exhibit increased numbers of B cells colonizing the thymus. Distinct intrathymic B cell subpopulations were identified, namely B220+, IgM+, CD23hi, CD21int cells; B220+, IgM+, CD23lo, CD21lo cells; and a population of B220+, IgM+, CD23lo, CD21hi cells. Anatomically, CD19+ B cells accumulated in the thymic medulla region juxtaposed to Foxp3+ T cells. These intrathymic B cells engender Tregs. Indeed, thymic Treg development was diminished in both B cell–deficient BAFF-Tg chimeras, but also B cell–deficient wild-type chimeras. B cell Ag capture and presentation are critical in vivo events for Treg development. In the absence of B cell surface MHC class II expression, thymic expansion of BAFF-Tg Tregs was lost. Further to this, expansion of Tregs did not occur in BAFF-Tg/Ig hen egg lysozyme BCR chimeras, demonstrating a requirement for Ag specificity. Thus, we present a mechanism whereby intrathymic B cells, through the provision of cognate help, contribute to the shaping of the Treg repertoire.

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Section: Discussionmentioning

confidence: 86%

Section: Thymic B Cells Provide Cognate Help For the Expansion Of Natmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A Role for Intrathymic B Cells in the Generation of Natural Regulatory T Cells

Walters

Webster

Daley

et al. 2014

The Journal of Immunology

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“…More interestingly, it has been reported that DCs can be infected by influenza viruses in vitro (30). Because of the DC function to migrate continuously into the LN but also in the thymus (15) with or without having contact and being activated by an Ag, thymic DCs play a major role in establishing tolerance by negative selection of thymocytes and induction of Tregs (45). We hypothesized that DCs are the carrier cell type for influenza viruses.…”

Section: Discussionmentioning

confidence: 99%

Highly Pathogenic Influenza Virus Infection of the Thymus Interferes with T Lymphocyte Development

Vogel

Haasbach

Reiling

et al. 2010

The Journal of Immunology

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Highly pathogenic avian influenza viruses (HPAIVs) cause severe disease in humans. Still, the basis for their increased pathogenesis remains unclear. Additionally, the high morbidity in the younger population stays inexplicable, and the recent pandemic H1N1v outbreak in 2009 demonstrated the urgent need for a better understanding about influenza virus infection. In the present study, we demonstrated that HPAIV infection of mice not only led to lung destruction but also to functional damage of the thymus. Moreover, respiratory dendritic cells in the lung functioned as targets for HPAIV infection being able to transport infectious virus from the lung into the thymus. The pandemic H1N1 influenza virus was able to infect respiratory dendritic cells without a proper transport to the thymus. The strong interference of HPAIV with the immune system is especially devastating for the host and can lead to lymphopenia. In summary, from our data, we conclude that highly pathogenic influenza viruses are able to reach the thymus via dendritic cells and to interfere with T lymphocyte development. Moreover, this exceptional mechanism might not only be found in influenza virus infection, but also might be the reason for the increased immune evasion of some new emerging pathogens.

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“…30,31 Moreover, peripheral DCs migrate to the thymus where they present peripheral antigens. 32,33 Taken together, these observations suggest that DCs participate in the maturation of T cells and the generation of FoxP3 þ Tregs in the thymus. However, the depletion of DCs does not affect thymic T-cell maturation and FoxP3 þ Treg generation, suggesting that the contribution of DCs to these processes is minimal.…”

Section: Function Of Dcs In Cns Autoimmunitymentioning

confidence: 73%

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

2014

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Dendritic cells (DCs) are professional antigen-presenting cells that control the generation of adaptive immunity. Consequently, DCs have a central role in the induction of protective immunity to pathogens and also in the pathogenic immune response responsible for the development and progression of autoimmune disorders. Thus the study of the molecular pathways that control DC development and function is likely to result in new strategies for the therapeutic manipulation of the immune response. In this review, we discuss the role and therapeutic value of DCs in autoimmune diseases, with a special focus on multiple sclerosis. Cell Death and Differentiation (2015) 22, 215-224; doi:10.1038/cdd.2014; published online 29 August 2014 FactsDendritic cells (DCs) control central and peripheral tolerance through their effects on effector and regulatory T cells. Specific signaling pathways regulate the ability of different DC populations to promote effector and regulatory T-cell responses. Abnormalities in DC numbers, recruitment and function contribute to the pathology of multiple sclerosis (MS) and can be partially overcome by the use of disease-modifying therapies and the targeting of specific molecular pathways. Nanotechnology provides new tools for the modulation of DC activity in vivo and the therapeutic induction of antigenspecific tolerance in immune-mediated disorders. Open QuestionsAlthough DC populations that promote the development of forkhead box P3-positive (FoxP3 þ ) regulatory T cells (Tregs) have been identified, it is not yet clear whether these populations constitute separate tolerogenic DC lineages or represent alternative activation or maturation states of other DC populations. What are the different molecular pathways that control the DC's ability to prime effector or tolerogenic T-cell responses?There is an unmet clinical need for the development of methods for the efficient and consistent generation of tolerogenic DCs in vitro and in vivo that can be implemented in large-scale clinical setups.Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that control the activation and polarization of T cells into specific lineages and, consequently, the generation of antigen-specific antibody and T-cell responses. 1 In the context of an infectious challenge, the induction of pathogenspecific immune responses provides protective immunity to fight the infection. However, in the context of autoimmune diseases DCs regulate the balance between pathogenic and regulatory immune mechanisms, controlling disease onset and progression. Thus, DCs have a central role in the control of the adaptive immune response to pathogens and selftissues and therefore constitute potential targets for the therapeutic modulation of the immune response. In this review, we discus the role of DCs in autoimmune diseases, with a special emphasis on their role in the modulation of central nervous system (CNS) inflammation in MS. Received 12.6.14; accepted 23.6.14; Edited by H-U Simon; published online 29.8.14 Abbreviations: A...

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Dendritic cells in the thymus contribute to T-regulatory cell induction

Cited by 268 publications

References 58 publications

A Role for Intrathymic B Cells in the Generation of Natural Regulatory T Cells

A Role for Intrathymic B Cells in the Generation of Natural Regulatory T Cells

Highly Pathogenic Influenza Virus Infection of the Thymus Interferes with T Lymphocyte Development

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

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