KERATINOCYTE-DERIVED T-CELL COSTIMULATION INDUCES PREFERENTIAL PRODUCTION OF IL-2 AND IL-4 BUT NOT IFN-GAMMA

By using superantigens, we have found previously that keratinocytes ac tivated by lFN-gamma could serve as accessory cells, providing costimu latory signals needed to induce T cell proliferation. Here, we compare d the profile of cytokines produced by T cells stimulated in the prese nce of activated keratinocytes with the response seen using profession al APCs. When keratinocytes are used as accessory cells there is a spe cific defect in T cell IFN gamma production, whereas IL-2 and IL-4 are induced at levels comparable with those seen when professional APCs a re used as accessory cells. Because keratinocytes express BB-1, a CD28 -ligand distinct from B7-1 or B7-2 (which are found on professional AP Cs), we examined the possibility that the defect in IFN-gamma producti on might be a result of nonproductive CD28 engagement. However, even w hen the CD28 pathway is directly activated by a stimulatory mAb, there is no induction of lFN-gamma production in keratinocyte-supported cul tures. In these same cultures IL-2 production is increased 10-fold, th us demonstrating a specific deficiency in the induction of IFN-gamma r ather than a failure to respond to CD28 stimulation. Analysis by rever se transcriptase-PCR and ELISA for the inducible p40 chain of IL-12 re veals that keratinocytes produce little if any messenger RNA and no pr otein for IL-12 p40 compared with professional APCs. Addition of rIL-1 2 to keratinocyte-supported cultures restores IFN-gamma levels to thos e seen when professional APCs are present. Finally, when T cells are r estimulated and analyzed at later time points (10 to 14 days) we find a refinement in cytokine profiles: T cells stimulated in the presence of professional APCs produced the Th1 cytokines IL-2 and lFN-gamma, wh ereas T cells stimulated in the presence of activated keratinocytes pr oduced only the Th2 cytokine IL-4. The specific ability of keratinocyt es to induce a Th2 response seems most closely linked to their absence of IL-12 production, and may be important in the maintenance of perip heral tolerance to self-Ags or in the immune response to exogenous Ags , pathogens, or haptens encountered in skin.