CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function.

The role of natural CD4+CD25+ regulatory T (T reg) cells in the control of allergic asthma remains poorly understood. We explore the impact of T reg cell depletion on the allergic response in mice susceptible (A/J) or comparatively resistant (C3H) to the development of allergen-induced airway hyperresponsiveness (AHR). In C3H mice, anti-CD25-mediated T reg cell depletion before house dust mite treatment increased several features of the allergic diathesis (AHR, eosinophilia, and IgE), which was concomitant with elevated T helper type 2 (Th2) cytokine production. In similarly T reg cell-depleted A/J mice, we observed a moderate increase in airway eosinophilia but no effects on AHR, IgE levels, or Th2 cytokine synthesis. As our experiments suggested that T reg cell depletion in C3H mice before sensitization was sufficient to enhance the allergic phenotype, we characterized dendritic cells (DCs) in T reg cell-depleted C3H mice. T reg cell-depleted mice had increased numbers of pulmonary myeloid DCs with elevated expression of major histocompatibility complex class II, CD80, and CD86. Moreover, DCs from T reg cell-depleted mice demonstrated an increased capacity to stimulate T cell proliferation and Th2 cytokine production, which was concomitant with reduced IL-12 expression. These data suggest that resistance to allergen-driven AHR is mediated in part by CD4+CD25+ T reg cell suppression of DC activation and that the absence of this regulatory pathway contributes to susceptibility.

Altered gene expression profiles in nasal respiratory epithelium reflect stable versus acute childhood asthma.

BACKGROUND: Asthma is the most common chronic disease of childhood and has a strong genetic component. OBJECTIVE: To identify gene expression signatures that reflect asthma-related processes and to determine whether these genes were similar or distinct between stable asthma and acute exacerbations in childhood, we profiled gene expression patterns in nasal respiratory epithelial cells. METHODS: Children who had stable asthma (asthma-S; n = 10) and children experiencing an asthma exacerbation (asthma-E; n = 10) were recruited along with nonatopic children without asthma (n = 10). RNA was prepared from nasal respiratory epithelial cells isolated from each child, initially analyzed as pooled samples from the 3 groups, and further validated by using microarrays and RT-PCR with individual patient samples. RESULTS: Distinct gene clusters were identifiable in individual and pooled asthma-S and asthma-E samples. Asthma-E samples demonstrated the strongest and most reproducible signatures, with 314 genes of 34,886 measured as present on the chip demonstrating induction or repression of greater than 2-fold with P < .05 in each of 4 individual samples. Asthma-S-regulated genes encompassed genes that overlapped with those of asthma-E but were fewer (166) and less consistent with respect to their behavior across the asthma-E patient samples. CONCLUSION: Exacerbated asthma status is readily distinguished based on the occurrence of strong gene expression signatures in nasal epithelial samples. Stable asthma status also exhibits differential signatures. The results suggest that there are independent gene expression signatures reflective of cells and genes poised or committed to activation by an asthma attack.