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This article is part of the supplement: 25th European Workshop for Rheumatology Research

Poster presentation

The transcription T-bet is required for optimal proinflammatory trafficking of CD4+ T cells

RM Rao1, GM Lord2, H Choe3, AH Lichtman1, FW Luscinskas1 and LH Glimcher2

Author affiliations

1 Center of Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA

2 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA

3 Department of Pediatrics, Children's Hospital, Boston, Massachusetts, USA

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Citation and License

Arthritis Research & Therapy 2005, 7(Suppl 1):P5  doi:10.1186/ar1526

The electronic version of this article is the complete one and can be found online at:


Received:11 January 2005
Published:17 February 2005

© 2005 BioMed Central Ltd

Background

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.

Acknowledgements

This work was supported by the Arthritis Research Campaign (R0600), the Medical Research Council (G108/380) and the National Institutes of Health (AI48126, HL36028, HL53993).