The cytokine thymic stromal lymphopoietin (TSLP) has been linked to human allergic inflammatory diseases. We show here that TSLP expression was increased in the lungs of mice with antigen-induced asthma, whereas TSLP receptor-deficient mice had considerably attenuated disease. Lung-specific expression of a Tslp transgene induced airway inflammation and hyperreactivity characterized by T helper type 2 cytokines and increased immunoglobulin E. The lungs of Tslp-transgenic mice showed massive infiltration of leukocytes, goblet cell hyperplasia and subepithelial fibrosis. TSLP was capable of activating bone marrow-derived dendritic cells to upregulate costimulatory molecules and produce the T helper type 2 cell-attracting chemokine CCL17. These findings suggest that TSLP is an important factor necessary and sufficient for the initiation of allergic airway inflammation.

Dendritic cells (DCs) are professional antigen-presenting cells that have the ability to sense infection and tissue stress, sample and present antigen to T lymphocytes, and induce different forms of immunity and tolerance. The functional versatility of DCs depends on their remarkable ability to translate collectively the information from both the invading microbes and their resident tissue microenvironments and then make an appropriate immune response. Recent progress in understanding TLR biology has illuminated the mechanisms by which DCs link innate and adaptive antimicrobial immune responses. However, how tissue microenvironments shape the function of DCs has remained elusive. Recent studies of TSLP (thymic stromal lymphopoietin), an epithelial cell-derived cytokine that strongly activates DCs, provide evidence at a molecular level that epithelial cells/tissue microenvironments directly communicate with DCs. We review recent progress on how TSLP expressed within thymus and peripheral lymphoid and nonlymphoid tissues regulates DC-mediated central tolerance, peripheral T cell homeostasis, and inflammatory Th2 responses.

The cytokine thymic stromal lymphopoietin (TSLP) has recently been implicated in the pathogenesis of atopic dermatitis (AD) and other allergic diseases in humans. To further characterize its role in this disease process, transgenic mice were generated that express a keratinocyte-specific, tetracycline-inducible TSLP transgene. Skin-specific overexpression of TSLP resulted in an AD-like phenotype, with the development of eczematous lesions containing inflammatory dermal cellular infiltrates, a dramatic increase in Th2 CD4+ T cells expressing cutaneous homing receptors, and elevated serum levels of IgE. These transgenic mice demonstrate that TSLP can initiate a cascade of allergic inflammation in the skin and provide a valuable animal model for future study of this common disease.

T helper 9 (Th9) cells are specialized for the production of IL-9, promote allergic inflammation in mice, and are associated with allergic disease in humans. It has not been determined whether Th9 cells express a characteristic transcriptional signature. In this study, we performed microarray analysis to identify genes enriched in Th9 cells compared with other Th subsets. This analysis defined a transcriptional regulatory network required for the expression of a subset of Th9-enriched genes. The activator protein 1 (AP1) family transcription factor BATF (B cell, activating transcription factor-like) was among the genes enriched in Th9 cells and was required for the expression of IL-9 and other Th9-associated genes in both human and mouse T cells. The expression of BATF was increased in Th9 cultures derived from atopic infants compared with Th9 cultures from control infants. T cells deficient in BATF expression had a diminished capacity to promote allergic inflammation compared with wild-type controls. Moreover, mouse Th9 cells ectopically expressing BATF were more efficient at promoting allergic inflammation than control transduced cells. These data indicate that BATF is a central regulator of the Th9 phenotype and contributes to the development of allergic inflammation.

A cDNA homolog of the Drosophila melanogaster Broad Complex (BRC) gene was isolated from the tobacco hornworm, Manduca sexta, which shows a predicted 88% amino acid identity with Drosophila BRC in the N-terminal BTB domain. Three zinc finger domains encoding homologs of the Drosophila Z2, Z3, and Z4 domains (93, 100, and 85% identity, respectively) were obtained by RT-PCR. In Manduca dorsal abdominal epidermis, BRC RNAs were not observed during the larval molt. Three BRC transcripts-6.0, 7.0, and 9.0 kb-first appeared at the end of the feeding stage of the fifth (final) instar when the epidermis is exposed to ecdysteroids in the absence of juvenile hormone (JH) and becomes committed to pupal differentiation. These RNAs were induced in day 2 fifth larval epidermis in vitro by 20-hydroxyecdysone (20E) in the absence of JH with dose-response and time courses similar to the induction of pupal commitment. This induction by 20E in vitro was prevented by the presence of JH I at levels seen in vivo during the larval molt. In the wing discs, the BRC RNAs appeared shortly after ecdysis to the fifth instar and coincided with the onset of metamorphic competence of these discs. Application of a JH analogue pyriproxifen during the fourth instar molt delayed and reduced the levels of BRC mRNAs seen in the wing discs in the early fifth instar, but did not completely prevent their appearance in this tissue that first differentiates at metamorphosis. The expression of the BRC transcription factors thus appears to be one of the first molecular indications of the genetic reprogramming of the epidermis necessary for insect metamorphosis. How JH prevents BRC expression in this epidermis may provide the key to understanding how this hormone controls metamorphosis.