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Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice
Zhe Zhang, … , Thomas B. Clarke, Jeffrey N. Weiser
Zhe Zhang, … , Thomas B. Clarke, Jeffrey N. Weiser
Published June 8, 2009
Citation Information: J Clin Invest. 2009;119(7):1899-1909. https://doi.org/10.1172/JCI36731.
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Research Article Infectious disease

Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice

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Abstract

Microbial colonization of mucosal surfaces may be an initial event in the progression to disease, and it is often a transient process. For the extracellular pathogen Streptococcus pneumoniae studied in a mouse model, nasopharyngeal carriage is eliminated over a period of weeks and requires cellular rather than humoral immunity. Here, we demonstrate that primary infection led to TLR2-dependent recruitment of monocyte/macrophages into the upper airway lumen, where they engulfed pneumococci. Pharmacologic depletion of luminal monocyte/macrophages by intranasal instillation of liposomal clodronate diminished pneumococcal clearance. Efficient clearance of colonization required TLR2 signaling to generate a population of pneumococcal-specific IL-17–expressing CD4+ T cells. Depletion of either IL-17A or CD4+ T cells was sufficient to block the recruitment of monocyte/macrophages that allowed for effective late pneumococcal clearance. In contrast with naive mice, previously colonized mice showed enhanced early clearance that correlated with a more robust influx of luminal neutrophils. As for primary colonization, these cellular responses required Th17 immunity. Our findings demonstrate that monocyte/macrophages and neutrophils recruited to the mucosal surface are key effectors in clearing primary and secondary bacterial colonization, respectively.

Authors

Zhe Zhang, Thomas B. Clarke, Jeffrey N. Weiser

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Figure 5

Colonization with strain P1121 led to mucosal and systemic CD4+ T cell responses, which were attenuated in the absence of TLR2 signaling.

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Colonization with strain P1121 led to mucosal and systemic CD4+ T cell r...
Mice were colonized with strain P1121 (or sham colonized for naive animals) for 6 weeks, and T cell responses to P1121 were analyzed. (A) Systemic Th17 response in P1121-colonized WT but not Tlr2–/– mice. Splenocytes were stimulated ex vivo with heat-killed P1121 (MOI 50:1), and P1121-specific Th17 response was evaluated by quantification of CD45+– and CD4+–double-positive events through IL-17A intracellular cytokine staining analysis. Representative experiment showing responses in naive and previously colonized WT mice (upper panels) or Tlr2–/– mice (lower panels), with the numbers in the upper left-hand corner indicating the frequencies of IL-17A–producing CD4+ T cells. (B) Combined results of IL-17A intracellular cytokine staining of splenocytes in response to stimulation with heat-killed P1121 (hk-P1121), medium (negative control), and a combination of PMA (6 nM) and ionomycin (5 nM) (positive control [Pos]). (C) Mucosal T cell responses are blunted in Tlr2–/– mice. WT (black bars) or Tlr2–/– mice (white bars) were challenged with P1121 (primary) or rechallenged with P1121 for 1 day 6 weeks after precolonization (secondary). The number of CD4+ T cells at the mucosal surface was quantified by differential cell quantification of lymphocytes in cytospin preparations; n = 5 per group. (D) Representative experiment showing flow cytometric quantification of mucosal CD4+ T cells. Numbers of CD45+– and CD4+–double-positive events in pooled nasal washes are shown in the upper left-hand corners. n = 5 per group. *P < 0.05; **P < 0.01.

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