Strain-specific requirement for eosinophils in the recruitment of T cells to the lung during the development of allergic asthma

Eosinophils have been implicated as playing a major role in allergic airway responses. However, the importance of these cells to the development of this disease has remained ambiguous despite many studies, partly because of lack of appropriate model systems. In this study, using transgenic murine models, we more clearly delineate a role for eosinophils in asthma. We report that, in contrast to results obtained on a BALB/c background, eosinophil-deficient C57BL/6 ΔdblGATA mice (eosinophil-null mice via the ΔDblGATA1 mutation) have reduced airway hyperresponsiveness, and cytokine production of interleukin (IL)-4, -5, and -13 in ovalbumin-induced allergic airway inflammation. This was caused by reduced T cell recruitment into the lung, as these mouse lungs had reduced expression of CCL7/MCP-3, CC11/eotaxin-1, and CCL24/eotaxin-2. Transferring eosinophils into these eosinophil-deficient mice and, more importantly, delivery of CCL11/eotaxin-1 into the lung during the development of this disease rescued lung T cell infiltration and airway inflammation when delivered together with allergen. These studies indicate that on the C57BL/6 background, eosinophils are integral to the development of airway allergic responses by modulating chemokine and/or cytokine production in the lung, leading to T cell recruitment

Modeling Susceptibility versus Resistance in Allergic Airway Disease Reveals Regulation by Tec Kinase Itk

Murine models of allergic asthma have been used to understand the mechanisms of development and pathology in this disease. In addition, knockout mice have contributed significantly to our understanding of the roles of specific molecules and cytokines in these models. However, results can vary significantly depending on the mouse strain used in the model, and in particularly in understanding the effect of specific knockouts. For example, it can be equivocal as to whether specific gene knockouts affect the susceptibility of the mice to developing the disease, or lead to resistance. Here we used a house dust mite model of allergic airway inflammation to examine the response of two strains of mice (C57BL/6 and BALB/c) which differ in their responses in allergic airway inflammation. We demonstrate an algorithm that can facilitate the understanding of the behavior of these models with regards to susceptibility (to allergic airway inflammation) (Saai) or resistance (Raai) in this model. We verify that both C57BL/6 and BALB/c develop disease, but BALB/c mice have higher Saai for development. We then use this approach to show that the absence of the Tec family kinase Itk, which regulates the production of Th2 cytokines, leads to Raai in the C57BL/6 background, but decreases Saai on the BALB/c background. We suggest that the use of such approaches could clarify the behavior of various knockout mice in modeling allergic asthma

Differential Regulation of Cytokine Production by CD1d-Restricted NKT Cells in Response to Superantigen Staphylococcal Enterotoxin B Exposure

NKT cells are a heterogeneous population characterized by the ability to rapidly produce cytokines, such as interleukin 2 (IL-2), IL-4, and gamma interferon (IFN-γ) in response to infections by viruses, bacteria, and parasites. The bacterial superantigen staphylococcal enterotoxin B (SEB) interacts with T cells bearing the Vβ3, -7, or -8 T-cell receptors, inducing their expansion and cytokine secretion, leading to death in some cases due to cytokine poisoning. The majority of NKT cells bear the Vβ7 or -8 T-cell receptor, suggesting that they may play a role in regulating this response. Using mice lacking NKT cells (CD1d(−/−) and Jα18(−/−) mice), we set out to identify the role of these cells in T-cell expansion, cytokine secretion, and toxicity induced by exposure to SEB. We find that Vβ8(+) CD4(+) T-cell populations similarly expand in wild-type (WT) and NKT cell-null mice and that NKT cells did not regulate the secretion of IL-2. By contrast, these cells positively regulated the secretion of IL-4 and IFN-γ production and negatively regulated the secretion of tumor necrosis factor alpha (TNF-α). However, this negative regulation of TNF-α secretion by NKT cells provides only a minor protective effect on SEB-mediated shock in WT mice compared to mice lacking NKT cells. These data suggest that NKT cells may regulate the nature of the cytokine response to exposure to the superantigen SEB and may act as regulatory T cells during exposure to this superantigen

Itk regulates the development of susceptibility or resistance to allergic airway inflammation dependent on background.

<p>A) Model of data analysis. Strain 1 and 2 differ with regards to their dose response to allergen. This difference can be captured by the slope of their dose response (Left panel), the significance of which can inform on whether there is a response (<i>p</i><0.05) or not (<i>p</i>>0.05) (right panel). These <i>p</i> values can be used as described in the text to determine resistance (<i>R</i>), i.e. no response (with <i>p</i>>0.05,) or the degrees of susceptibility (with <i>p</i><0.05), which is related to the slope of their response, and thus the <i>p</i> values of those slopes. <b>B</b>) Analysis of the slopes of the IL-4, IL-13 and IFN-γ (left panel) or CCL-7 and CCL-11 (middle panel) dose responses for the indicated mice. Analysis of the inverse of the slopes of the data shown in (A) (right panel, note log scales on the y-axis). <b>C</b>) Analysis of Susceptible (<i>S_aai</i>) or Resistance (<i>R_aai</i>) as described in the<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0011348#s4" target="_blank">materials and methods</a> . The dotted line indicates the cutoff of 0.77 between resistance and susceptibility. <b>D</b>) Hierarchical clustering of the values in (C) to generate a cluster tree (B6 = C57BL/6; Bc = BALB/c; B6/Itk^−/− =  C57BL/6/Itk^−/−; Bc/Itk^−/− =  BALB/c/Itk^−/−).</p

(A) Immunized ΔdblGATA mice were given CCL11/eotaxin-1 during challenge with OVA

Alternatively, immunized WT C57BL/6 or ΔdblGATA mice were just given CCL11/eotaxin. This was followed by AHR analysis by mechanical ventilation ( = 4, repeated 2 times). *, P < 0.05 for ΔdblGATA + Eot/OVA versus WT or ΔdblGATA + Eot alone. (B) Lungs from immunized and i.n. OVA-challenged WT and ΔdblGATA mice or ΔdblGATA mice delivered eotaxin-1 with OVA, were analyzed for CD4 T cells. Some mice challenged with eotaxin/OVA also received anti-CCL11 blocking antibody i.n. ( = 4 mice/group, repeated 2 times). *, P < 0.05 WT versus ΔdblGATA + OVA. Error bars are ± the SEM.<p><b>Copyright information:</b></p><p>Taken from "Strain-specific requirement for eosinophils in the recruitment of T cells to the lung during the development of allergic asthma"</p><p></p><p>The Journal of Experimental Medicine 2008;205(6):1285-1292.</p><p>Published online 9 Jun 2008</p><p>PMCID:PMC2413027.</p><p></p

Strain-specific requirement for eosinophils in the recruitment of T cells to the lung during the development of allergic asthma-6

for OVA-challenged mice; = 4 Sham). *, P < 0.02 for WT and ΔdblGATA ± Eos versus PBS groups. (B) Mouse lungs from WT, ΔdblGATA, or ΔdblGATA + eosinophils treated as in , and analyzed by HE or PAS stain. Bars, 50 μm.<p><b>Copyright information:</b></p><p>Taken from "Strain-specific requirement for eosinophils in the recruitment of T cells to the lung during the development of allergic asthma"</p><p></p><p>The Journal of Experimental Medicine 2008;205(6):1285-1292.</p><p>Published online 9 Jun 2008</p><p>PMCID:PMC2413027.</p><p></p