title: Murine Fibroblastic Reticular Cells From Lymph Node Interact With CD4+ T Cells Through CD40-CD40L.
abstract: BACKGROUND
  Costimulatory blockade with anti-CD40L monoclonal antibody (mAb) plus donor-specific splenocyte transfusion (DST) induces alloantigen-specific tolerance. We previously showed that lymphotoxin signaling in the fibroblastic reticular cell (FRC) stromal subset was required for proper lymph node structure and function during tolerization in murine cardiac transplantation. Here we focused on FRC functions and hypothesized that DST and anti-CD40L mAb-modulated FRC interactions with CD4(+) T cells in mice.
  
  
  METHODS
  Mice were immunized or tolerized by DST or DST plus anti-CD40L mAb. Fibroblastic reticular cells were flow-sorted at different timepoints for characterization and in vitro proliferation and activation assays.
  
  
  RESULTS
  Fibroblastic reticular cells responded rapidly to DST by transcribing inflammatory cytokine and chemokine messenger RNAs, such as CXCL2, CXCL9, CXCL10, and CCL21. Conversely, anti-CD40L mAb inhibited FRC inflammatory responses. CD40 was expressed on FRC and agonistic anti-CD40 mAb activated FRC, which supported CD4(+) T-cell proliferation, whereas unstimulated FRC did not. Anti-CD3 mAb-activated CD4(+) T cells induced inflammatory cytokine and chemokine expressions by FRC, which were inhibited by anti-CD40L mAb. Thus, FRC phenotype was altered by interaction with CD4(+) T cells through CD40-CD40L, and activated FRC interacted directly with CD4(+) T cells to support T cell activation and proliferation in vitro.
  
  
  CONCLUSIONS
  Taken together, these results demonstrated that CD40 on FRC facilitated bidirectional communication between FRC and CD4(+) T cells via CD40-CD40L, thereby altering FRC gene expression of immune regulatory molecules. Because blockade of CD40-CD40L interactions results in tolerance in mice, identification of FRC-T cell interactions provides a new research target for tolerance induction.
authors: 1 Center for Vascular and Inflammatory Diseases, University of Maryland, Baltimore, MD. 2 Departments of Surgery, University of Maryland, Baltimore, MD. 3 Microbiology and Immunology, University of Maryland, Baltimore, MD.
authors: Yumi
authors: Y
authors: Nakayama
authors: C Colin
authors: CC
authors: Brinkman
authors: Jonathan S
authors: JS
authors: Bromberg
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism*; D023201:CD40 Ligand / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D007108:Immune Tolerance; D018836:Inflammation Mediators / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D016207:Cytokines; D018836:Inflammation Mediators; D023201:CD40 Ligand