stromal cells; lymph node; T cell homeostasis; T cell activation; Secondary lymphoid tissues; architecture; homeostasis; inflammation; dendritic cell function; chemokines; cytokines; extracellular matrix
Chai Qian, Onder Lucas, Scandella Elke, Gil-Cruz Cristina, Perez-Shibayama Christian, Cupovic Jovana, Danuser Renzo, Sparwasser Tim, Luther Sanjiv A, Thiel Volker, Rülicke Thomas, Stein Jens V, Hehlgans Thomas, Ludewig Burkhard (2013), Maturation of lymph node fibroblastic reticular cells from myofibroblastic precursors is critical for antiviral immunity., in Immunity
, 38(5), 1013-24.
Weber Michele, Hauschild Robert, Schwarz Jan, Moussion Christine, de Vries Ingrid, Legler Daniel F, Luther Sanjiv A, Bollenbach Tobias, Sixt Michael (2013), Interstitial dendritic cell guidance by haptotactic chemokine gradients., in Science (New York, N.Y.)
, 339(6117), 328-32.
Siegert Stefanie, Luther Sanjiv A (2012), Positive and negative regulation of T cell responses by fibroblastic reticular cells within paracortical regions of lymph nodes., in Frontiers in immunology
, 3, 285-285.
Matter Matthias S, Hilmenyuk Tamara, Claus Christina, Marone Romina, Schürch Christian, Tinguely Marianne, Terracciano Luigi, Luther Sanjiv A, Ochsenbein Adrian F (2011), Destruction of lymphoid organ architecture and hepatitis caused by CD4+ T cells., in PloS one
, 6(9), e24772-1-e24772-13.
Siegert Stefanie, Huang Hsin-Ying, Yang Chen-Ying, Scarpellino Leonardo, Carrie Lucie, Essex Sarah, Nelson Peter J, Heikenwalder Matthias, Acha-Orbea Hans, Buckley Christopher D, Marsland Benjamin J, Zehn Dietmar, Luther Sanjiv A (2011), Fibroblastic reticular cells from lymph nodes attenuate T cell expansion by producing nitric oxide., in PloS one
, 6(11), e27618-1-e27618-14.
Luther Sanjiv A, Vogt Tobias K, Siegert Stefanie (2011), Guiding blind T cells and dendritic cells: A closer look at fibroblastic reticular cells found within lymph node T zones., in Immunology letters
, 138(1), 9-11.
Link A, Hardie DL, Favre S, Britschgi MR, Adams DH, Sixt M, Cyster JG, Buckley CD, Luther SA (2011), Association of T-Zone Reticular Networks and Conduits with Ectopic Lymphoid Tissues in Mice and Humans, in AMERICAN JOURNAL OF PATHOLOGY
, 178(4), 1662-1675.
Huang Hsin-Ying, Luther Sanjiv A, Expression and function of interleukin-7 in secondary and tertiary lymphoid organs., in Seminars in immunology
Kania Gabriela, Siegert Stefanie, Behnke Silvia, Prados-Rosales Rafael, Casadevall Arturo, Lüscher Thomas F, Luther Sanjiv A, Kopf Manfred, Eriksson Urs, Blyszczuk Przemyslaw, Innate Signalling Promotes Formation of Regulatory Nitric Oxide-Producing Dendritic Cells Limiting T Cell Expansion in Experimental Autoimmune Myocarditis., in Circulation
1. Summary of the research proposalIt is within the T cell rich zone of secondary lymphoid organs (SLO) that dendritic cells (DC) present the captured pathogens to recirculating T cells in order to activate the rare antigen-specific T cells. While we have made considerable progress in understanding the biology of DC and T lymphocytes, we know very little about the reticular stromal cells that form the ‘niches’ within the T zone. T zone fibroblastic reticular cells (TRC) were recently shown to produce a sponge-like cellular network that serves as a ‘road system’ for migrating lymphocytes. Over the last six years my laboratory has developed the technology to isolate, culture and characterize stromal cells of the T zone at the phenotypic and functional level. We could demonstrate that these TRC are a distinct mesenchymal cell type with active functions for the adaptive immune system, as they control the size of the peripheral T cell pool and the encounters with DC. My laboratory is now in an excellent position to further dissect the phenotype, regulation and function of these poorly characterized TRC. Therefore, our four major aims focus on improving our understanding of the role of the T zone microenvironment and TRC in particular for the homeostasis and activation of the adaptive immune system. Aim 1: Cells and signals regulating TRC homeostasis and IL-7 expression in lymph nodesThe number of TRC and their IL-7 expression level must be strictly regulated as together they control the size of the peripheral T cell pool. We wish to gain insight into this regulation by investigating the role of lymphocytes, DC and cytokines in this process.Aim 2: In vitro characterization of the role of TRC for T cell activationTo be able to study TRC regulation and function in a highly accessible system, we have established B6 TRC lines that we can coculture with antigen-presenting DC and T cells. As we have observed that TRC initially delay T cell activation, we aim to establish whether this effect is TRC-specific and identify the mechanism and molecules involved. Aim 3: Characterization of the TRC reaction during immune response and LN swelling Preliminary results suggest that TRC numbers strongly increase during LN swelling, concordant with the increase in T cell numbers. We plan to characterize the phenotype, number, turnover and organization of TRC during the course of the immune response and investigate the cells and factors involved. Another focus will be to identify novel functions of activated versus naïve TRC by looking at the transcriptional profile.