Mucosally delivered dendritic cells activate T cells independently of IL-12 and endogenous APCs.
In vitro manipulated dendritic cells (DC) have increasingly been used as a promising vaccine formulation against cancer and infectious disease. However, improved understanding of the immune mechanisms is needed for the development of safe and efficacious mucosal DC immunization. We have developed a murine model of respiratory mucosal immunization by using a genetically manipulated DC vaccine. Within 24 h of intranasal delivery, the majority of vaccine DCs migrated to the lung mucosa and draining lymph nodes and elicited a significant level of T cells capable of IFN-gamma secretion and CTL in the airway lumen as well as substantial T cell responses in the spleen. And such T cell responses were associated with enhanced protection against respiratory mucosal intracellular bacterial challenge. In comparison, parenteral i.m. DC immunization did not elicit marked airway luminal T cell responses and immune protection regardless of strong systemic T cell activation. Although repeated mucosal DC delivery boosted Ag-specific T cells in the airway lumen, added benefits to CD8 T cell activation and immune protection were not observed. By using MHC-deficient vaccine DCs, we further demonstrated that mucosal DC immunization-mediated CD8 and CD4 T cell activation does not require endogenous DCs. By using IL-12-deficient vaccine DCs, we also observed that IL-12(-/-) DCs failed to migrate to the lymph nodes but remained capable of T cell activation. Our observations indicate that mucosal delivery of vaccine DCs represents an effective approach to enhance mucosal T cell immunity, which may operate independent of vaccine IL-12 and endogenous DCs.
McCormick
Sarah
S
Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, and M. G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
Santosuosso
Michael
M
Small
Cherrie-Lee
CL
Shaler
Christopher R
CR
Zhang
Xizhong
X
Jeyanathan
Mangalakumari
M
Mu
Jingyu
J
Takenaka
Shunsuke
S
Ngai
Patricia
P
Gauldie
Jack
J
Wan
Yonghong
Y
Xing
Zhou
Z
D000217:Acyltransferases / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D000281:Administration, Intranasal; D019264:Adoptive Transfer / Q000379:methods; D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D001426:Bacterial Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology / Q000637:transplantation; D004195:Disease Models, Animal; D005260:Female; D005822:Genetic Vectors; D018664:Interleukin-12 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009297:Nasal Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D018664:Interleukin-12; D000217:Acyltransferases; C121433:antigen 85B, Mycobacterium tuberculosis