dendritic cell; mouse models; cancers; self-tolerance; intravital imaging; lymph node stromal cells; autoimmune diseases; lymphoid organs; T lymphocyte
HumbertMarion, GueryLeslie, BrighouseDale, LemeilleSylvain, HuguesStephanie (2018), Intratumoral CpG-B Promotes Antitumoral Neutrophil, cDC, and T-cell Cooperation without Reprograming Tolerogenic pDC, in Cancer Research
, 78(12), 3280-3292.
Nunes-Hasler Paula, Maschalidi Sophia, Lippens Carla, Castelbou Cyril, Bouvet Samuel, Guido Daniele, Bermont Flavien, Bassoy Esen Y., Page Nicolas, Merkler Doron, Hugues Stéphanie, Martinvalet Denis, Manoury Bénédicte, Demaurex Nicolas (2017), STIM1 promotes migration, phagosomal maturation and antigen cross-presentation in dendritic cells, in Nature Communications
, 8(1), 1852-1852.
Molica Filippo, Meens Merlijn J., Dubrot Juan, Ehrlich Avigail, Roth Christel L., Morel Sandrine, Pelli Graziano, Vinet Laurent, Braunersreuther Vincent, Ratib Osman, Chanson Marc, Hugues Stephanie, Scemes Eliana, Kwak Brenda R. (2017), Pannexin1 links lymphatic function to lipid metabolism and atherosclerosis, in Scientific Reports
, 7(1), 13706-13706.
Meens Merlijn J., Kutkut Issa, Rochemont Viviane, Dubrot Juan, Kaladji Fouad R., Sabine Amélie, Lyons Oliver, Hendrikx Stefanie, Bernier-Latmani Jeremiah, Kiefer Friedemann, Smith Alberto, Hugues Stéphanie, Petrova Tatiana V., Kwak Brenda R. (2017), Cx47 fine-tunes the handling of serum lipids but is dispensable for lymphatic vascular function, in PLOS ONE
, 12(7), e0181476-e0181476.
Menezes Shinelle, Melandri Daisy, Anselmi Giorgio, Perchet Thibaut, Loschko Jakob, Dubrot Juan, Patel Rajen, Gautier Emmanuel L., Hugues Stéphanie, Longhi M. Paula, Henry Jake Y., Quezada Sergio A., Lauvau Grégoire, Lennon-Duménil Ana-Maria, Gutiérrez-Martínez Enrique, Bessis Alain, Gomez-Perdiguero Elisa, Jacome-Galarza Christian E., Garner Hannah, Geissmann Frederic, Golub Rachel, Nussenzweig Michel C., Guermonprez Pierre (2016), The Heterogeneity of Ly6Chi Monocytes Controls Their Differentiation into iNOS+ Macrophages or Monocyte-Derived Dendritic Cells, in Immunity
, 45(6), 1205-1218.
Sarter Kerstin, Sarter Kerstin (2016), Btn2a2, a T cell immunomodulatory molecule coregulated with MHC class II genes, in J Exp Med
Hepworth MR Fung TC Masur SH Kelsen JR McConnell FM Dubrot J Withers DR Hugues S Farrar MA, Hepworth MR Fung TC Masur SH Kelsen JR McConnell FM Dubrot J Withers DR Hugues S Farrar MA (2015), Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4⁺ T cells., in Science
Duraes FV Niven J Dubrot J Hugues S Gannagé M., Duraes FV Niven J Dubrot J Hugues S Gannagé M. (2015), Macroautophagy in Endogenous Processing of Self- and Pathogen-Derived Antigens for MHC Class II Presentation., in Frontiers in Immunology
Chalmin F Rochemont V Lippens C Clottu A Sailer AW Merkler D Hugues S Pot C, Chalmin F Rochemont V Lippens C Clottu A Sailer AW Merkler D Hugues S Pot C (2015), Oxysterols regulate encephalitogenic CD4(+) T cell trafficking during central nervous system autoimmunity., in Journal of Autoimmunity
Lippens Carla, Lippens Carla, IDO-orchestrated crosstalk between pDCs and Tregs inhibits autoimmunity., in Journal if autoimmunity
Guéry L. Hugues S., Guéry L. Hugues S., New role for antigen-presenting activated pDCs in promoting Th17 cells and impacting antitumor immunity., in Oncoimmunology
Duraes FV Lippens C Steinbach K Dubrot J Brighouse D Bendriss-Vermare N Issazadeh-Navikas S M, Duraes FV Lippens C Steinbach K Dubrot J Brighouse D Bendriss-Vermare N Issazadeh-Navikas S M, pDC therapy induces recovery from EAE by recruiting endogenous pDC to sites of CNS inflammation., in Journal of Autoimmunity
The main mediators of immunity are B and T lymphocytes, but their function is under the control of dendritic cells (DC). DC in the periphery capture and process antigens (Ag), express lymphocyte co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses. They not only activate lymphocytes, they also tolerize T cells to Ag that are innate to the body (self-antigens), thereby minimizing autoimmune reactions. Once a neglected cell type, DC can now be readily obtained in sufficient quantities to allow molecular and cell biological analysis. It has become increasingly evident that these cells are a powerful tool for manipulating the immune system. DC are generally classified as either conventional (cDC) or plasmacytoid (pDC). It is well established that cDC function as sentinels of the adaptive immune system. They reside in peripheral tissues, sample their surroundings and migrate to secondary lymphoid tissues to present foreign or host Ag to T cells. Under neutral or non-inflammatory conditions, cDC are, paradoxically, able to induce initially a transient activation of host Ag-specific T cells followed by a rapid shutdown of these T cells resulting in tolerance. Inflammatory immune responses, however, cause DC maturation and results in rapid and effective T cell responses. In contrast to cDC, pDC were initially believed to be involved primarily in innate, or first-line, immune responses via the secretion of type I interferons following viral or bacterial infections. However, very recent findings demonstrate that like cDC, pDC are also implicated in adaptive immune responses. Exciting new developments in pDC biology further implicates these cells directly in the induction of T cell tolerance, a key process in avoiding autoimmunity. Thus, nature has developed a unique system of whereby the hosts immune response, via pDC, present Ag to potentially autoimmune-inducing T cells in order for them to be rendered anergic or non-responsive. These processes are at the infancy of being elucidated and further work will potentially open new avenues to the therapeutic treatment, via pDC manipulation, in the aim of controlling debilitating autoimmune diseases. This proposal will allow the intricate in vivo analysis of the impact on immune responses following the selective loss of Ag presentation function by pDC. In particular, the pDC involvement in the generation and maintenance of a tolerogenic state in diseases will be investigated. The mechanisms that allow for pDC-induced T cell tolerance and, thus, protect the host from autoimmunity, will be dissected.These models of tolerance involving cDC and/or pDC limit the presentation of particular Ags to the lymph nodes draining the tissues in which the Ag is expressed. An alternative mechanism, involving non-hematopoietic lymph node stromal cells (LNSC), has recently emerged. Indeed, these cells were recently shown to not only function as passive conduits in lymph nodes, but also to contribute to peripheral T cell responses. First, they produce soluble mediators that indirectly alter T cell and DC functions and consequently impact T cell responses. Second, they endogenously express self-Ags - a feature thought to be restricted to medullary thymic epithelial cells- and present these self-Ags to CD8+ T cells to induce their deletion, thus contributing to CD8+ T cell tolerance. Whether LNSC can similarly impact CD4+ T cell responses is totally unknown. One exciting hypothesis we are testing that LNSC present Ag to CD4+ T cells and directly impact peripheral CD4+ T cell responses.This work entails the use of cutting edge techniques (including two-photon intravital imaging on live animals) and animal models of disease (e.g. multiple sclerosis, autoimmune diabetes, tumors) to dissect the mechanisms that allow for hematopoietic and non-hematopoietic Ag presenting cells-induced T cell tolerance and, thus, protect the host from autoimmunity and cancers. The main objective of this study is to define new molecular and cellular biomarkers and, thus, identify potential therapeutic targets for manipulating the immune system in the treatment of debilitating autoimmune diseases. A further objective of the proposal is to expand these studies into oncology and to understand why some tumors are not efficiently eradicated by the immune system.