No abstract

Key Points Human blood BDCA-1+ DCs have precursor potential. TSLP can be implicated in LC ontogenesis during inflammation.

Dendritic cells (DCs) need to migrate in the interstitial environment of peripheral tissues to reach secondary lymphoid organs and initiate a suitable immune response. Whether and how inflamed tissues instruct DCs to emigrate is not fully understood. In this study, we report the unexpected finding that the epithelialderived cytokine TSLP triggers chemokinesis of resting primary human DCs in a cell-autonomous manner. TSLP induced the polarization of both microtubule and actin cytoskeletons and promoted DC 3-dimensional migration in transwell as well as in microfabricated channels that mimic the confined environment of peripheral tissues. TSLP-induced migration relied on the actin-based motor myosin II and was inhibited by blebbistatin. Accordingly, TSLP triggered the redistribution of phosphorylated myosin II regulatory light chain to the actin cortex, indicating that IntroductionCompetence of dendritic cells (DCs) to induce the differentiation of naive T cells into effector T cells relies on their ability to migrate from the peripheral sites of inflammation to the secondary lymphoid organs where T-cell priming takes place. 1,2 During this process, DCs must emigrate out of peripheral tissue and move through a variety of narrow spaces, such as tight intercellular junctions in epithelia, basal membrane, extracellular matrix, and endothelia. This motility is in part orchestrated by chemokine gradients, such as CCL19 or CCL21, which dictate the directionality of the movement toward lymphoid organs where these chemokines are abundantly expressed. 3 Whether endogenous signals produced by injured tissue at the inflammatory site can instruct DCs to migrate is currently unknown.Cytokines are proteins that act through specific surface receptors to modulate critical cellular functions, such as cell proliferation, differentiation, and survival. 4 They are important components of the inflammatory microenvironment. Their precise function in inducing or modulating cell migration has not been elucidated. Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that strongly activates DCs and initiates a Th2 type of CD4 T-cell response. 5 It plays a critical role in allergic diseases and, in particular, atopic dermatitis where it is highly produced by keratinocytes in human lesions 6 and mouse models. 7,8 Thus, TSLP mediates a cross-talk between inflamed epithelia and the innate immune response. 5 Previous studies from our group and others suggested that TSLP may be associated with Langerhans cell migration in situ 6 and ex vivo. 9 In this study, we demonstrate that TSLP is sufficient to induce the polarization, and 3-dimensional and confined migration of human DC in vitro, through the actin-based motor protein, myosin II. This constitutes a novel property of cytokines in triggering a cell-autonomous DC migration in interstitial spaces. Methods Blood DC purification and cultureCD11c ϩ DCs were purified to 99% by FACS sorting from buffy coats of healthy adult volunteer blood donors (Crozatier Blood Bank) as prev...