Mechanisms of Mucosal and Parenteral Tuberculosis Vaccinations: Adenoviral-Based Mucosal Immunization Preferentially Elicits Sustained Accumulation of Immune Protective CD4 and CD8 T Cells within the Airway Lumen

Abstract

The mechanisms underlying better immune protection by mucosal vaccination have remained poorly understood. In our current study we have investigated the mechanisms by which respiratory virus-mediated mucosal vaccination provides remarkably better immune protection against pulmonary tuberculosis than parenteral vaccination. A recombinant adenovirus-based tuberculosis (TB) vaccine expressing Mycobacterium tuberculosis Ag85A (AdAg85A) was administered either intranasally (i.n.) or i.m. to mice, and Ag-specific CD4 and CD8 T cell responses, including frequency, IFN-γ production, and CTL, were examined in the spleen, lung interstitium, and airway lumen. Although i.m. immunization with AdAg85A led to activation of T cells, particularly CD8 T cells, in the spleen and, to a lesser extent, in the lung interstitium, it failed to elicit any T cell response in the airway lumen. In contrast, although i.n. immunization failed to effectively activate T cells in the spleen, it uniquely elicited higher numbers of Ag-specific CD4 and CD8 T cells in the airway lumen that were capable of IFN-γ production and cytolytic activities, as assessed by an intratracheal in vivo CTL assay. These airway luminal T cells of i.n. immunized mice or splenic T cells of i.m. immunized mice, upon transfer locally to the lungs of naive SCID mice, conferred immune protection against M. tuberculosis challenge. Our study has demonstrated that the airway luminal T cell population plays an important role in immune protection against pulmonary TB, thus providing mechanistic insights into the superior immune protection conferred by respiratory mucosal TB vaccination.

Vaccine against tuberculosis: what’s new?

“…demonstrated that intranasal AdAg85a was able to elicit robust mucosal CD4 + and CD8 + T-cells responses in the airway lumen [34,36]. …”

Impact of Recombinant Adenovirus Serotype 35 Priming versus Boosting of aPlasmodium falciparumProtein: Characterization of T- and B-Cell Responses to Liver-Stage Antigen 1

“…In this regard, heterologous prime-boost vaccination schedules are highly attractive, since they can expand and activate both arms of the immune system. Ad vectors have been extensively used in the development of vaccines against diseases where a strong T-cell response is required (3,43,45,47). They are particularly attractive because of their intrinsic ability to induce a strong T-cell response characterized by high levels of IFN-␥ and cytotoxic activity (59).…”

Pulmonary Mycobacterial Granuloma

“…Mice were first bled via the abdominal vessels and their lungs were exhaustively lavaged with PBS to remove bronchoalveolar lavage cells following our previously described protocol. 23 Lung granulomas were then isolated by using a well-established protocol. 24 -26 Briefly, the lavaged lungs were homogenized in a tissue blender (Waring Commercial, Torrington, CT) using the low speed setting for 10 to 15 seconds, which leaves the granulomas intact.…”

“…23,24,26 Purified airway luminal and granuloma cells were stained with antibodies against CD3, CD4, CD8, CD19, CD11c, Gr.1, CD11b, or NK1.1 and analyzed by FACS. The FACS analysis revealed the presence of CD3ϩCD4 ϩ (CD4 T cells), CD3ϩCD8ϩ (CD8 T cells), CD3-CD19ϩ (B cells), CD3-NK1.1ϩ [natural killer (NK) cells], CD11cϩ-CD11bϩ/Ϫ (CD11cϩ APCs), CD11c-CD11bϩ (CD11bϩ APCs), and CD11c-Gr.1ϩ (neutrophils) cell populations in both the airway lumen and granuloma (Table 1).…”