Thymic stromal lymphopoietin (TSLP) is an IL-7 related cytokine, produced by

Thymic stromal lymphopoietin (TSLP) is an IL-7 related cytokine, produced by epithelial cells, that has been linked to atopic dermatitis and asthma; however, it remains unclear how TSLP shapes the adaptive immune response that causes these allergic disorders. chemokines CCL17 and CCL22 (1,2). TSLP-treated human DCs induce a unique inflammatory Th2 cytokine profile in CD4 T cells, specifically production of IL-4, IL-5, IL-13 and TNF (1,2). In addition, it has been shown that TSLP can act directly on CD4 T cells to drive IL-4 production (6,8). However, much of this data was generated from studies, and there is very little known regarding the cellular targets of TSLP. Consistent with its ability to drive Th2-type responses and by a keratinocyte cell line(a) Relative TSLP mRNA expression in ears following sensitization with 0.5% FITC in A-769662 distributor vehicle (acetone/dibutyl phthalate), vehicle alone, 0.5% FITC in acetone, acetone alone, or untreated ears. The leftmost two columns show TSLP mRNA induction after treatment of ears with acetone alone (gray) or 0.5% FITC in acetone (black). Significant upregulation of TSLP message 24 H post 1:1 acetone/DBP (vehicle) or FITC (diluted in vehicle) treatment relative to untreated or FITC in acetone control (** 0.01, Wilcoxon test, n=15). (b) Serum IgE levels in untreated or FITC sensitized and challenged WT or TSLPR?/? mice. WT mice have significantly higher basal and post-challenge serum IgE levels (** 0.01, Wilcoxon test, n9 for each group). TSLPR?/? Mice Exhibit Impaired Skin-Derived DC Migration after Epicutaneous Hapten Sensitization TSLP treatment of DCs has been shown to induce increased expression of co-stimulatory molecules, and to generate DCs capable of promoting Th2 cell differentiation (2,10). However, very little is known about the effect of TSLP on DCs during an immune response data, and the finding that human epidermal Langerhans cells have been shown to express TSLPR and respond to TSLP treatment (34), we hypothesized that skin-resident DCs would be a target of TSLP during the sensitization phase of a CHS response. To initiate an adaptive immune response tissue-resident DCs undergo a series of processes that include antigen uptake, maturation, migration to draining lymph nodes, and presentation of antigen to T cells (35). To A-769662 distributor determine if the failure of TSLPR?/? mice to develop a CHS response to FITC was due to a deficit in DC function, we first assessed the migration of DCs to draining lymph nodes following FITC sensitization (Fig. 4A). Skin draining inguinal and axillary lymph node cells from FITC-sensitized WT and TSLPR?/? mice were analyzed for the relative frequency and absolute numbers of FITC+CD11c+ cells (Fig. 4B and C). There was a significant reduction in frequency and number of FITC+CD11c+ DCs in the draining lymph nodes of TSLPR?/? mice 24 H post sensitization (Fig. 4B A-769662 distributor and C). As shown previously, we observed a requirement for DBP in driving the migration of skin-resident DCs to the draining LN, as there Rabbit Polyclonal to GABRD were essentially no FITC+CD11c+ cells after treatment with FITC in acetone alone (data not shown) (29). Open in a separate window Physique 4 Reduced accumulation of FITC+CD11c+ cells in skin draining lymph nodes of TSLPR?/? mice 24 H post-sensitization with FITC in acetone/DBP(a) Representative FACS plots from skin-draining inguinal and axillary lymph node cells from WT and TSLPR?/? mice 24 H post-sensitization around the abdomen with 0.5% FITC, after Percoll enrichment for low density cells. Values represent frequency of FITC+CD11c+ cells within the live cell gate. (b) Frequency and (c) absolute number of FITC+CD11c+ cells found in inguinal and axillary LN of WT and TSLPR?/? mice 24 H post FITC sensitization. TSLPR?/? FITC+CD11c+ cell frequency and number are significantly reduced compared to WT. (* 0.01, * 0.05, Wilcoxon test, representative of three independent experiments, n3 mice per group) Acute Blockade of TSLP Abrogates FITC-Induced Contact Hypersensitivity The data presented above is consistent with an essential role for TSLP signaling in a Th2 CHS response. However, as the studies were performed using mice genetically deficient for the TSLP receptor, it is formally possible that, in the absence of TSLP signals there is a developmental defect resulting in reduced Th2 responses. As TSLP expression is seen most prominently at barrier surfaces (skin, gut, and lung) under steady-state conditions, the loss of a constant, albeit.