IL-2 linked to a peptide from influenza hemagglutinin enhances T cell activation by affecting the antigen-presentation function of bone marrow-derived dendritic cells

Chimeric proteins containing antigen linked to cytokines haveshown some promise as vaccine candidates but little is knownof their mechanism of action, particularly at the level of theantigen-presenting cell. We have investigated this using a chimericprotein in which an immunodominant T cell epitope from influenzahemagglutinin peptide (HA), recognized in the context of I-E^d,was fused to IL-2. Immature murine dendritic cells (DC) derivedfrom bone marrow (BMDC) were used to present the chimeric proteinto a T cell hybridoma with TCR specific for the HA peptide (A5cell line). HA–IL-2 was found to induce significantlyhigher T cell activation than HA alone. Although the inclusionof IL-2 and HA separately did increase the response of A5 cellscompared to HA alone, they were not as effective as the HA–IL-2chimeric protein. When an antibody known to block IL-2 receptor chain (CD25) was included, A5 activation was reduced, suggestinga role for the receptor in this process. Expression of CD25on A5 cells was low during activation, implying that the effectwas mediated by CD25⁺ BMDC. Antigen uptake and processing ofHA–IL-2 by BMDC was required since fixing BMDC, priorto antigen exposure, greatly reduced their ability to activateA5 cells. The function of CD25 on DC is currently unknown. Ourresults suggest this receptor may play a role in antigen uptakeand subsequent T cell activation by receptor-mediated endocytosisof antigen attached to IL-2. This finding that may have implicationsfor the development of a new generation of vaccines.