title: LFA-1 co-stimulation inhibits T(h)2 differentiation by down-modulating IL-4 responsiveness.
abstract: Initial T cell activation in the context of different co-stimulatory receptors can influence subsequent lineage commitment into T(h) effector cell subtypes. Specifically, CD28 co-stimulation promotes T(h)2 differentiation, whereas leukocyte function-associated antigen-1 (LFA-1) co-stimulation promotes T(h)1 differentiation and inhibits T(h)2 differentiation. In this report, we have addressed the mechanism of LFA-1-mediated inhibition of T(h)2 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 T(h)2 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 T(h)2 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 T(h)2 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 T(h)2 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 T(h)2 differentiation, increasing the effective concentration of IL-4 required to drive T(h)2 responses.
authors.affiliation: 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.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Jenks
authors.forename: Bartholomew J
authors.initials: BJ
authors.lastname: Eisfelder
authors.forename: Jim
authors.initials: J
authors.lastname: Miller
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism* / Q000494:pharmacology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D010766:Phosphorylation; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4