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dc.contributor.authorRao, RM
dc.contributor.authorLord, GM
dc.contributor.authorChoe, H.
dc.contributor.authorLichtman, AH
dc.contributor.authorLuscinskas, FW
dc.contributor.authorGlimcher, Laurie Hollis
dc.date.accessioned2012-02-13T20:35:49Z
dc.date.issued2005
dc.identifier.citationRao, RM, GM Lord, H Choe, AH Lichtman, FW Luscinskas, and LH Glimcher. 2005. The transcription T-bet is required for optimal proinflammatory trafficking of CD4+ T cells. Poster presented at the 25th European Workshop for Rheumatology Research, Glasgow UK. Arthritis Research & Therapy 7(Suppl 1): P5.en_US
dc.identifier.issn1478-6354en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:8160713
dc.description.abstractBackground: The transcription factor T-bet is a critical regulator of Th1 effector function. Animals deficient in T-bet are protected from a variety of inflammatory diseases, including systemic lupus erythematosus and inflammatory arthritis. An essential function of Th1 cells is the ability to traffic appropriately to sites of inflammation, which is largely dependent on the expression of specific selectin ligands and chemokine receptors. We therefore hypothesised that T-bet would modulate lymphocyte trafficking in vitro and in vivo by direct regulation of both selectin binding and chemokine function. Methods: Balb/c mice deficient in, or transgenic for, T-bet had been generated previously. T-bet\(^{-/-}\) × DO11.10 TCR and T-bet\(^{-/-}\) × IFN\(^{-/-}\) mice were generated by backcrossing for >10 generations. CD4\(^+\) T cells were generated from primary lymph nodes from all these mice by positive selection and stimulation with appropriate antigen. Functional analysis used the following four methods: adoptive transfer into WT Balb/c mice, which were then injected with OVA, cells were harvested from the spleen, lymph node and peritoneum; selectin binding, interactions with immoblised P-selectin and E-selectin under conditions of laminar flow were examined in a parallel plate flow chamber; expression of selectin ligands, using flow cytometry, real-time PCR and 35S incorporation; and chemokine receptor expression and function, using flow cytometry, real-time PCR, transwell chemotaxis and endothelial binding under flow conditions. Results: Selective migration of T-bet\(^{-/-}\) CD4\(^+\) T cells in a Th1-dependent model of peritoneal inflammation was completely abrogated. Further investigation revealed that this effect was due to a 50% reduction in binding to P-selectin but not E-selectin under in vitro flow conditions and that this was as a result of impaired tyrosine sulfation of PSGL-1. In addition, mRNA and surface expression of CXCR3, but not CCR5, was reduced and this was associated with a reduction in both transwell chemotaxis and binding to endothelial cells. Retroviral transfer experiments of T-bet cDNA into T-bet\(^{-/-}\) and T-bet\(^{-/-}\) × IFN\(^{-/-}\) cells demonstrated that these effects were independent of interferon. Conclusions: These data establish that T-bet imprints a specific migratory program onto developing CD4\(^+\) cells via control of PSGL-1 sulfation (and thus P-selectin binding) and CXCR3 expression and function. Furthermore, as E-selectin and CCR5 binding are unimpaired, this reveals a level of control on trafficking of Th1 lymphocytes not recognised by previous paradigms.en_US
dc.language.isoen_USen_US
dc.publisherBioMed Centralen_US
dc.relation.isversionofdoi:10.1186/ar1526en_US
dash.licenseLAA
dc.titleThe Transcription T-bet is Required for Optimal Proinflammatory Trafficking of CD4+ T Cellsen_US
dc.typeConference Paperen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalArthritis Research & Therapyen_US
dash.depositing.authorGlimcher, Laurie Hollis
dc.date.available2012-02-13T20:35:49Z
dash.affiliation.otherSPH^Immunology and Infectious Diseases Immunologyen_US
dash.affiliation.otherSPH^Immunology and Infectious Diseases TPHen_US
dash.affiliation.otherHMS^Medicine-Brigham and Women's Hospitalen_US
dc.identifier.doi10.1186/ar1526*
dash.contributor.affiliatedGlimcher, Laurie


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