International Immunology Advance Access originally published online on February 7, 2005
International Immunology 2005 17(3):315-323; doi:10.1093/intimm/dxh211
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LFA-1 co-stimulation inhibits Th2 differentiation by down-modulating IL-4 responsiveness
1 David H. Smith Center for Vaccine Biology and Immunology, Aab Institute, Department of Microbiology and Immunology, University of Rochester, Box 609, 601 Elmwood Avenue, Rochester, NY 14642, USA
2 Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637, USA
Correspondence to: J. Miller; E-mail: jim_miller{at}urmc.rochester.edu
Initial T cell activation in the context of different co-stimulatory receptors can influence subsequent lineage commitment into Th effector cell subtypes. Specifically, CD28 co-stimulation promotes Th2 differentiation, whereas leukocyte function-associated antigen-1 (LFA-1) co-stimulation promotes Th1 differentiation and inhibits Th2 differentiation. In this report, we have addressed the mechanism of LFA-1-mediated inhibition of Th2 responses. We show that co-stimulation through LFA-1 does not decrease early IL-4 secretion, but rather induces a loss in IL-4 responsiveness. T cells primed in the context of LFA-1 co-stimulation require a 5-fold increase in the concentration of IL-4 required to drive Th2 differentiation, which is not mediated by a loss in IL-4R expression. To determine whether LFA-1 co-stimulation impacts on proximal signaling from the IL-4R, we first identified a kinetic window where we could separate IL-4-driven Th2 differentiation from initial T cell priming. T cells were primed for 2 days under different co-stimulation conditions and re-cultured in the presence of IL-4. Subsequent Th2 differentiation was absolutely dependent on addition of IL-4. Proximal IL-4R signaling, as evidenced by tyrosine phosphorylation of signal transducer and activator of transcription-6 (STAT6), was not inhibited by initial co-stimulation through LFA-1, yet these T cells still required higher amounts of IL-4 and corresponding higher levels of STAT6 activation to up-regulate GATA-3 and induce Th2 differentiation. Thus, LFA-1 co-stimulation appears to interfere with GATA-3 expression downstream of STAT6. These results suggest that LFA-1 co-stimulation functions as a threshold modulator of Th2 differentiation, increasing the effective concentration of IL-4 required to drive Th2 responses.
Keywords: cytokine receptors, GATA-3, signal transduction, STAT6, Th1/Th2 cells
* These authors contributed equally to this work.
Transmitting editor: K. Murphy
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