Transport of Bacillus anthracis from the lungs to the draining lymph nodes is a rapid process facilitated by CD11c+ cells.

Inhalational anthrax is established after inhaled Bacillus anthracis spores are transported to the lung associated lymph nodes. Dendritic cells (CD11c+ cells) located in the lungs are phagocytes that maintain many capabilities consistent with transport. This study investigates the role of dendritic cells as conduits of spores from the lung to the draining lymph nodes. The intratracheally spore-challenged mouse model of inhalational anthrax was utilized to investigate in vivo activities of CD11c+ cells. FITC labeled spores were delivered to the lungs of mice. Subsequently lung associated lymph nodes were isolated after infection and CD11c+ cells were found in association with the labeled spores. Further investigation of CD11c+ cells in early anthrax events was facilitated by use of the CD11c-diphtheria toxin (DT) receptor-green fluorescent protein transgenic mice in which CD11c+ cells can be transiently depleted by treatment with DT. We found that the presence of CD11c+ cells was necessary for efficient traffic of the spore to lung associated lymph nodes at early times after infection. Cultured dendritic cells were used to determine that these cells are capable of B. anthracis spore phagocytosis, and support germination and outgrowth. This data demonstrates that CD11c+ cells are likely carriers of B. anthracis spores from the point of inhalation in the lung to the lung associated lymph nodes. The cultured dendritic cell allows for spore germination and outgrowth supporting the concept that the CD11c+ cell responsible for this function can be a dendritic cell.

Modulation of the pulmonary type 2 T-cell response to Cryptococcus neoformans by intratracheal delivery of a tumor necrosis factor alpha-expressing adenoviral vector.

C57BL/6 mice develop an allergic bronchopulmonary mycosis following intratracheal inoculation of Cryptococcus neoformans 24067. We determined that only low levels of tumor necrosis factor alpha (TNF-alpha) are produced in the lungs following infection. Thus, the objective of the present studies was to determine whether treatment with a TNF-alpha-expressing adenoviral vector (adenoviral vector with the murine TNF-alpha transgene under the control of the human cytomegalovirus promoter [AdTNFalpha]) could switch the type 2 (T2) T-cell response/T1 T-cell response balance toward the T1 T-cell response. AdTNFalpha induced an increase in TNF-alpha expression at days 3 and 7. At days 7 to 14, the number of cryptococcal lung CFU continued to increase in both untreated and control adenoviral vector (empty adenovirus type 5 backbone)-treated mice, but the number was ultimately 100-fold lower following AdTNFalpha treatment. AdTNFalpha markedly increased neutrophil and macrophage numbers, and pulmonary eosinophilia did not develop. CXCL1, CXCL2, and gamma interferon were also up-regulated, while eotaxin, interleukin-4 (IL-4), and IL-5 were down-regulated. AdTNFalpha treatment also increased the number of CD80(+) and CD40(+) cells and decreased the number of CD86(+) cells (CD11b(+) and CD11c(+)) in the lungs. Major histocompatibility complex class II levels on CD11b(+) cells were increased. Whole-lung expression of inducible nitric oxide synthase was increased, while YM2 expression and acidic mammalian chitinase expression were decreased. None of these effects were observed with the control (empty) adenoviral vector. Overall, these results support the hypothesis that early TNF-alpha expression promotes a shift in T-cell and macrophage polarization from T2/alternatively activated macrophages toward T1/classically activated macrophages, resulting in control of the fungal infection and prevention of the allergic response.