title: T-cell-receptor-dependent signal intensity dominantly controls CD4(+) T cell polarization In Vivo.
abstract: Polarization of effector CD4(+) T cells can be influenced by both antigen-specific signals and by pathogen- or adjuvant-induced cytokines, with current models attributing a dominant role to the latter. Here we have examined the relationship between these factors in shaping cell-mediated immunity by using intravital imaging of CD4(+) T cell interactions with dendritic cells (DCs) exposed to polarizing adjuvants. These studies revealed a close correspondence between strength of T cell receptor (TCR)-dependent signaling and T helper 1 (Th1) versus Th2 cell fate, with antigen concentration dominating over adjuvant in controlling T cell polarity. Consistent with this finding, at a fixed antigen concentration, adjuvants inducing Th1 cells operated by affecting DC costimulation that amplified TCR signaling. TCR signal strength controlled downstream cytokine receptor expression, linking the two components in a hierarchical fashion. These data reveal how quantitative integration of antigen display and costimulation regulates downstream checkpoints responsible for cytokine-mediated control of effector differentiation.
authors: Lymphocyte Biology Section, Laboratory of Systems Biology, NIAID, NIH, Bethesda, MD 20892, USA. Electronic address: vanpanhuysn@niaid.nih.gov.
authors: Nicholas
authors: N
authors: van Panhuys
authors: Institute of Pathology, Charité University Hospital, 10117 Berlin, Germany.
authors: Frederick
authors: F
authors: Klauschen
authors: Lymphocyte Biology Section, Laboratory of Systems Biology, NIAID, NIH, Bethesda, MD 20892, USA. Electronic address: rgermain@niaid.nih.gov.
authors: Ronald N
authors: RN
authors: Germain
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D019264:Adoptive Transfer; D000818:Animals; D020013:Calcium Signaling / Q000276:immunology; D002450:Cell Communication / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D016764:Cell Polarity / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010206:Papain / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D008070:Lipopolysaccharides; D011948:Receptors, Antigen, T-Cell; D010206:Papain