Lymph node–resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation
Jarish N. Cohen,Cynthia J. Guidi,Eric F. Tewalt,Hui Qiao,Sherin J. Rouhani,Alanna Ruddell,Andrew G. Farr,Kenneth S. K. Tung,Victor H. Engelhard +8 more
TLDR
It is demonstrated that LN-resident lymphatic endothelial cells express multiple peripheral tissue antigens (PTAs) independent of the autoimmune regulator (Aire), and that other LN stromal subpopulations express distinct PTAs by mechanisms that vary in their Aire dependence.Abstract:
Peripheral immune tolerance is generally thought to result from cross-presentation of tissue-derived proteins by quiescent tissue-resident dendritic cells to self-reactive T cells that have escaped thymic negative selection, leading to anergy or deletion. Recently, we and others have implicated the lymph node (LN) stroma in mediating CD8 T cell peripheral tolerance. We demonstrate that LN-resident lymphatic endothelial cells express multiple peripheral tissue antigens (PTAs) independent of the autoimmune regulator (Aire). They directly present an epitope derived from one of these, the melanocyte-specific protein tyrosinase, to tyrosinase-specific CD8 T cells, leading to their deletion. We also show that other LN stromal subpopulations express distinct PTAs by mechanisms that vary in their Aire dependence. These results establish lymphatic endothelial cells, and potentially other LN-resident cells, as systemic mediators of peripheral immune tolerance.read more
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Cross-presentation by dendritic cells.
Olivier Joffre,Elodie Segura,Elodie Segura,Ariel Savina,Ariel Savina,Sebastian Amigorena,Sebastian Amigorena +6 more
TL;DR: Recent advances in the understanding of the intracellular mechanisms of cross-presentation are summarized and its role in immunity and tolerance in the context of specialization between DC subsets is discussed.
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The lymphatic vasculature in disease
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Immunological hallmarks of stromal cells in the tumour microenvironment
TL;DR: Evidence thatStromal determinants interact with leukocytes and influence antitumour immunity is discussed, with emphasis on the immunological attributes of stromal cells that may foster their protumorigenic function.
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Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes
Morganna Freeman-Keller,Young-Chul Kim,Heather Cronin,Allison Richards,Geoffrey T. Gibney,Jeffrey S. Weber +5 more
TL;DR: Cutaneous irAEs are associated with improved survival in melanoma patients treated with nivolumab, and clinical benefit should be validated in larger prospective analyses.
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New insights into the development of lymphoid tissues.
TL;DR: New insights into the earliest phases of peripheral lymph node and Peyer's patch formation that occur before lymphotoxin-β receptor signalling are discussed and a role for the developing nervous system is suggested.
References
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Journal ArticleDOI
Dendritic Cells Induce Peripheral T Cell Unresponsiveness under Steady State Conditions in Vivo
Daniel Hawiger,Kayo Inaba,Kayo Inaba,Yair Dorsett,Ming Guo,Karsten Mahnke,Miguel Rivera,Jeffrey V. Ravetch,Ralph M. Steinman,Michel C. Nussenzweig,Michel C. Nussenzweig +10 more
TL;DR: An antigen delivery system targeting these specialized antigen presenting cells in vivo using a monoclonal antibody to a DC-restricted endocytic receptor is devised, which concludes that in the absence of additional stimuli DCs induce transient antigen-specific T cell activation followed by T cell deletion and unresponsiveness.
Journal ArticleDOI
Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self.
TL;DR: It is found that this promiscuous gene expression was a cell-autonomous property of medullary epithelial cells and was maintained during the entire period of thymic T cell output, which may facilitate tolerance induction to self-antigens that would otherwise be temporally or spatially secluded from the immune system.
Journal ArticleDOI
Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells.
Alexander Link,Tobias K. Vogt,Stéphanie Favre,Mirjam R. Britschgi,Hans Acha-Orbea,Boris Hinz,Jason G. Cyster,Sanjiv A. Luther +7 more
TL;DR: It is suggested that lymph nodes and T zone fibroblastic reticular cells have a key function in naive CD4+ and CD8+ T cell homeostasis by providing a limited reservoir of survival factors.
Journal ArticleDOI
A central role for central tolerance
Bruno Kyewski,Ludger Klein +1 more
TL;DR: This review summarizes current knowledge on the cellular and molecular regulation of TRA expression in mTECs, outlines relevant mechanisms of antigen presentation and modes of tolerance induction, and discusses implications for the pathogenesis of autoimmune diseases and other biological processes such as fertility, pregnancy, puberty, and tumor defense.
Class I-restricted Cross-Presentation of Exogenous Self-Antigens Leads to Deletion of Autoreactive
TL;DR: In this article, the authors showed that cross-presentation of self-antigens can lead to the peripheral deletion of autoreactive CD8 1 T cells (OT-I cells).