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 have shown some promise as vaccine candidates but little is known of their mechanism of action, particularly at the level of the antigen-presenting cell. We have investigated this using a chimeric protein in which an immunodominant T cell epitope from influenza hemagglutinin peptide (HA), recognized in the context of I-E(d), was fused to IL-2. Immature murine dendritic cells (DC) derived from bone marrow (BMDC) were used to present the chimeric protein to a T cell hybridoma with TCR specific for the HA peptide (A5 cell line). HA-IL-2 was found to induce significantly higher T cell activation than HA alone. Although the inclusion of IL-2 and HA separately did increase the response of A5 cells compared to HA alone, they were not as effective as the HA-IL-2 chimeric protein. When an antibody known to block IL-2 receptor alpha chain (CD25) was included, A5 activation was reduced, suggesting a role for the receptor in this process. Expression of CD25 on A5 cells was low during activation, implying that the effect was mediated by CD25(+) BMDC. Antigen uptake and processing of HA-IL-2 by BMDC was required since fixing BMDC, prior to antigen exposure, greatly reduced their ability to activate A5 cells. The function of CD25 on DC is currently unknown. Our results suggest this receptor may play a role in antigen uptake and subsequent T cell activation by receptor-mediated endocytosis of antigen attached to IL-2. This finding that may have implications for the development of a new generation of vaccines.
Faulkner
L
L
Department of Microbiology, University of Otago, PO Box 56, Dunedin, New Zealand.
Buchan
G
G
Lockhart
E
E
Slobbe
L
L
Wilson
M
M
Baird
M
M
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D017951:Antigen Presentation / Q000276:immunology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005557:Formaldehyde / Q000494:pharmacology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology* / Q000378:metabolism; D007252:Influenza Vaccines / Q000276:immunology; D007376:Interleukin-2 / Q000378:metabolism / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000276:immunology*; D011108:Polymers / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D000276:Adjuvants, Immunologic; D019138:Antibodies, Blocking; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D007376:Interleukin-2; D010446:Peptide Fragments; D011108:Polymers; D015375:Receptors, Interleukin-2; D005557:Formaldehyde; C003043:paraform