Role of B7-CD28/CTLA-4 costimulation and NF-kappa B in allergen-induced T cell chemotaxis by IL-16 and RANTES

The mechanisms that cause T cell recruitment into inflamed airways of asthm atic individuals are poorly understood. It has been shown previously that b oth natural exposure to allergen and challenge in the laboratory induce T c ell accumulation in the bronchial mucosa of sensitized asthmatics, To study the mechanisms involved in this process, we have used an explant model in which bronchial biopsies taken from mild atopic asthmatic volunteers during fiberoptic bronchoscopy were stimulated in culture for 24 h bg the common aeroallergen house dust mite (Dermatophagoides pteronyssinus (Der p)), Anal ysis of culture supernatants showed that stimulation with Der p significant ly enhanced both the generation of T cell chemotactic activity by the mucos al tissue, as assayed in microchemotaxis chambers, and the production of IL -16 and RANTES. Neutralization experiments showed that IL-16 contributed mo re to the chemotactic activity than RANTES. The fusion protein CTLA-4-Ig, b locking B7:CD28 costimulation, and dexamethasone both significantly reduced the ex vivo production of chemotactic activity and release of IL-16 and RA NTES. The proteasome inhibitor Cbz-Ile-Glu(OtBu)-Ala-leucinal also had a si gnificant inhibitory effect on T cell chemotactic activity and IL-16 but no t RANTES generation, indicating a role for nuclear factor NF kappa B activa tion. These results indicate that allergen stimulates cells within the bron chial mucosa to increase IL-16 and RANTES release, both of which contribute to T cell accumulation in asthmatic airways. The allergen-induced chemotac tic activity is dependent on cell activation via CD28 and involves, at leas t partly, NF-kappa B.