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Abstract: The present study was designed to elucidate the role of TLR2, TLR4 and dectin-1 in the production of IL-12p40 by bone marrow-derived dendritic cells (BM-DCs) infected with Penicillium marneffei. IL-12p40 production was almost completely abrogated in BM-DCs from TLR2 gene-knockout (KO) and MyD88KO mice, but not from TLR4-defective C3H/HeJ mice compared to those from control mice. Furthermore, BM-DCs from dectin-1KO mice faintly produced IL-12p40 upon stimulation with this fungus. Using a luciferase reporter assay, P. marneffei activated NF-κB in HEK293 cells transfected with the TLR2 gene, but not with the dectin-1 gene, and their co-transfection did not lead to further increase in this response. These results indicate that TLR2 and dectin-1 are essential in sensing P. marneffei for the activation of BM-DCs. [Copyright &y& Elsevier]

Abstract: Previously, we demonstrated that Vα14+ NKT cells and IFN-γ are important upstream components in neutrophil-mediated host defense against infection with Streptococcus pneumoniae. In the present study, we extended these findings by elucidating the role of IFN-γ in this Vα14+ NKT cell-promoted process. Administration of recombinant IFN-γ to Jα18KO mice prolonged the shortened survival, promoted the attenuated clearance of bacteria and improved the reduced accumulation of neutrophils and synthesis of MIP-2 and TNF-α in the lungs, in comparison to wild-type (WT) mice. In addition, intravenous transfer of liver mononuclear cells (LMNC) from WT mice into Jα18KO mice resulted in complete recovery of the depleted responses listed above, whereas such effects were not detected when LMNC were obtained from IFN-γKO or Jα18KO mice. Activation of Vα14+ NKT cells by α-galactosylceramide (α-GalCer) significantly enhanced the clearance of bacteria, accumulation of neutrophils and synthesis of MIP-2 and TNF-α in the infected lungs; this effect was significantly inhibited by a neutralizing anti-IFN-γ antibody. Finally, in a flow cytometric analysis, TNF-α synthesis was detected largely by CD11bbright+ cells in the infected lungs. Our results demonstrated that IFN-γ plays an important role in the neutrophil-mediated host protective responses against pneumococcal infection promoted by Vα14+ NKT cells. [Copyright &y& Elsevier]

Abstract: The present study was designed to elucidate the role of Vγ4+ γδ T cells, a major subset of pulmonary γδ T cells, in host defense against infection with Streptococcus pneumoniae. The proportion and number of whole γδ T cells, identified as CD3+ and TCR-δ+ cells, and Vγ4+ γδ T cells, identified as CD3+ and TCR-Vγ4+ cells, increased in the lungs at 3, 6 and 12h post-infection. Survival of infected mice and lung bacterial clearance were severely impaired in TCR-Vγ4−/− mice compared with control wild-type (WT) mice. The impaired host protection in TCR-Vγ4−/− mice correlated well with attenuated recruitment of neutrophils in lungs. MIP-2 and TNF-α synthesis in the infected tissues was significantly reduced in TCR-Vγ4−/− mice compared with WT mice. Similar results were noted in the synthesis of TNF-α, but not clearly of MIP-2, by lung leukocytes stimulated with live bacteria. Our results demonstrate that Vγ4+ γδ T cells play an important role in the neutrophil-mediated host defense against S. pneumoniae infection by promoting the synthesis of TNF-α and possibly of MIP-2 in the lungs. [Copyright &y& Elsevier]

Abstract: CD1d-restricted NKT cells are reported to play a critical role in the host defense to pulmonary infection with Pseudomonas aeruginosa. However, the contribution of a major subset expressing a Vα14-Jα18 gene segment remains unclear. In the present study, we re-evaluated the role of NKT cells in the neutrophilic inflammatory responses and host defense to this infection using mice genetically lacking Jα18 or CD1d (Jα18KO or CD1dKO mice). These mice cleared the bacteria in lungs at a comparable level to wild-type (WT) mice. There was no significant difference in the local neutrophilic responses, as shown by neutrophil counts and synthesis of MIP-2 and TNF-α, in either KO mice from those in WT mice. Administration of α-galactosylceramide, a specific activator of Vα14+ NKT cells, failed to promote the bacterial clearance and neutrophilic responses, although the same treatment increased the synthesis of IFN-γ, suggesting the involvement of this cytokine downstream of NKT cells. In agreement against this notion, these responses were not further enhanced by administration of recombinant IFN-γ in the infected Jα18KO mice. Our data indicate that NKT cells play a limited role in the development of neutrophilic inflammatory responses and host defense to pulmonary infection with P. aeruginosa. [Copyright &y& Elsevier]