title: Lymph node stromal cells negatively regulate antigen-specific CD4+ T cell responses.
abstract: Lymph node (LN) stromal cells (LNSCs) form the functional structure of LNs and play an important role in lymphocyte survival and the maintenance of immune tolerance. Despite their broad spectrum of function, little is known about LNSC responses during microbial infection. In this study, we demonstrate that LNSC subsets display distinct kinetics following vaccinia virus infection. In particular, compared with the expansion of other LNSC subsets and the total LN cell population, the expansion of fibroblastic reticular cells (FRCs) was delayed and sustained by noncirculating progenitor cells. Notably, newly generated FRCs were preferentially located in perivascular areas. Viral clearance in reactive LNs preceded the onset of FRC expansion, raising the possibility that viral infection in LNs may have a negative impact on the differentiation of FRCs. We also found that MHC class II expression was upregulated in all LNSC subsets until day 10 postinfection. Genetic ablation of radioresistant stromal cell-mediated Ag presentation resulted in slower contraction of Ag-specific CD4(+) T cells. We propose that activated LNSCs acquire enhanced Ag-presentation capacity, serving as an extrinsic brake system for CD4(+) T cell responses. Disrupted function and homeostasis of LNSCs may contribute to immune deregulation in the context of chronic viral infection, autoimmunity, and graft-versus-host disease.
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan; Japan Science and Technology Agency, Tokyo 102-8666, Japan; Theodor Kocher Institute, University of Bern, CH-3012 Bern, Switzerland;
authors.forename: Jun
authors.initials: J
authors.lastname: Abe
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan; Japan Science and Technology Agency, Tokyo 102-8666, Japan;
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Shichino
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan; Japan Science and Technology Agency, Tokyo 102-8666, Japan;
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueha
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan; Japan Science and Technology Agency, Tokyo 102-8666, Japan; Division of Nephrology, Department of Laboratory Medicine, Kanazawa University, Ishikawa 920-1192, Japan;
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Hashimoto
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; and.
authors.forename: Michio
authors.initials: M
authors.lastname: Tomura
authors.affiliation: Japan Science and Technology Agency, Tokyo 102-8666, Japan; Center for Matrix Biology and Medicine, Graduate School of Medicine, Institute of Medical Sciences, Tokai University, Kanagawa 259-1143, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Inagaki
authors.affiliation: Theodor Kocher Institute, University of Bern, CH-3012 Bern, Switzerland;
authors.forename: Jens V
authors.initials: JV
authors.lastname: Stein
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan; Japan Science and Technology Agency, Tokyo 102-8666, Japan; koujim@m.u-tokyo.ac.jp.
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D018122:B7-1 Antigen / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002454:Cell Differentiation / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007108:Immune Tolerance; D019012:Integrin beta1 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000166:cytology* / Q000821:virology; D053259:Lymphotoxin beta Receptor / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010227:Parabiosis; D017479:Receptors, Platelet-Derived Growth Factor / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology; D017154:Stromal Cells / Q000276:immunology*; D014615:Vaccinia / Q000276:immunology; D014616:Vaccinia virus / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: D018122:B7-1 Antigen; C476399:Cd44 protein, mouse; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D018960:Hyaluronan Receptors; D019012:Integrin beta1; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D019010:Vascular Cell Adhesion Molecule-1; D017479:Receptors, Platelet-Derived Growth Factor