Protective anti-mycobacterial T cell responses through exquisite in vivo activation of vaccine-targeted dendritic cells

• Published in: European journal of immunology Vol. 38; no. 5; pp. 1247 - 1256
• Main Authors: Kamath, Arun T, Valenti, Mario P, Rochat, Anne-Françoise, Agger, Else M, Lingnau, Karen, von Gabain, Alexander, Andersen, Peter, Lambert, Paul-Henri, Siegrist, Claire-Anne
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley-VCH Verlag 01.05.2008; WILEY‐VCH Verlag
• Subjects: Adjuvant; Adjuvants, Immunologic - administration & dosage; Adjuvants, Immunologic - analysis; Alum Compounds - administration & dosage; Animals; Antigen Presentation - immunology; Antigens, Bacterial - genetics; Antigens, Bacterial - immunology; Antigens, CD - analysis; Antigens, CD - metabolism; Bacterial Proteins - genetics; Bacterial Proteins - immunology; CD11c Antigen - analysis; CD4-Positive T-Lymphocytes - immunology; Cell Proliferation; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; In vivo study; Interferon-gamma - metabolism; Interleukin-12 Subunit p40 - metabolism; Lymph nodes; Lymph Nodes - cytology; Lymph Nodes - immunology; Lymphocyte Activation - immunology; Mice; Mice, Inbred C57BL; Mycobacterium bovis - immunology; Oligodeoxyribonucleotides - pharmacology; Ovalbumin - administration & dosage; Ovalbumin - immunology; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - analysis; Recombinant Fusion Proteins - immunology; Spleen - cytology; Spleen - immunology; Spleen - microbiology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tuberculosis - immunology; Tuberculosis - prevention & control; Vaccination; Vaccination - methods
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200737889

Vaccine efficacy largely depends upon DC targeting and activation. The most potent TLR soluble ligands induce diffuse DC activation, which may be associated with marked pro-inflammatory responses and possibly adverse effects. This raises the concern that effective vaccine adjuvants may similarly rely on widespread DC activation. Using a promising candidate vaccine against tuberculosis (fusion protein of Ag85B and 6-kDa early secretory antigenic target (ESAT-6)) formulated in the potent IC31® adjuvant, DC targeting and activation was studied in vivo, following the fate of antigen and adjuvant in the draining lymph nodes, to define the magnitude of DC targeting/activation required in vivo to induce protective vaccine responses. Unexpectedly, protective IFN-γ-mediated Ag85B-ESAT-6/IC31® responses were associated to the activation of a minute population (less than 0.3%) of CD11c⁺ lymph node DC, without detectable systemic pro-inflammatory responses. This activated peripheral tissue-derived DC population, characterized by enhanced CD80, CD86, CD40 and IL-12p40 expression, was only identified when focusing on adjuvant- or antigen-labeled CD11c⁺ DC, which were found to support T cell proliferation. Immunization with aluminum hydroxide adjuvant (Alum) resulted in a similar proportion of antigen-associated DC but without detectable enhancement of CD80, CD86, CD40 or IL-12p40 expression. Thus, potent protective IFN-γ-producing responses may be elicited by the exquisite activation of a minute number of in vivo targeted DC.