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...
In an inflammatory microenvironment, multiple cytokines may act on the same target cell, creating the possibility for combinatorial interactions. How these may influence the system-level function of a given cytokine is unknown. Here we show that a single cytokine, interferon (IFN)-alpha, can generate multiple transcriptional signatures, including distinct functional modules of variable flexibility, when acting in four cytokine environments driving distinct T helper cell differentiation programs (Th0, Th1, Th2 and Th17). We provide experimental validation of a chemokine, cytokine and antiviral modules differentially induced by IFN-α in Th1, Th2 and Th17 environments. Functional impact is demonstrated for the antiviral response, with a lesser IFN-α-induced protection to HIV-1 and HIV-2 infection in a Th17 context. Our results reveal that a single cytokine can induce multiple transcriptional and functional programs in different microenvironments. This combinatorial flexibility creates a previously unrecognized diversity of responses, with potential impact on disease physiopathology and cytokine therapy.
Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that primes dendritic cells for Th2 induction. It has been implicated in different types of allergic diseases. Recent work suggested that TSLP could play an important role in the tumor microenvironment and influence tumor progression, in particular in breast cancer. In this study we systematically assessed the production of TSLP at the mRNA and protein levels in several human breast cancer cell lines, large-scale public transcriptomics data sets, and primary human breast tumors. We found that TSLP production was marginal, and concerned less than 10% of the tumors, with very low mRNA and protein levels. In most cases TSLP was undetectable and found to be expressed at lower levels in breast cancer as compared to normal breast tissue. Last, we could not detect any functional TSLP receptor (TSLPR) expression neither on hematopoietic cells nor on stromal cells within the primary tumor microenvironment. We conclude that TSLP-TSLPR pathway activity is not significantly detected within human breast cancer. Taken together, these observations do not support TSLP targeting in breast cancer.
Multiple myeloma (MM) is a haematologic malignancy characterized by the expansion of monoclonal plasma cells in the bone marrow. It is associated with serum or urine monoclonal protein and organ damage including renal failure, anaemia, hypercalcaemia and bone lesions. Despite recent improvements MM still remains an incurable disease. Previous studies have shown that the adoptive transfer of autologous T-cells modified to express chimeric antigen receptors (CAR) is effective in cases of acute and chronic lymphoid leukaemia. However, the adjustment of CAR-T-cell therapy to MM is hindered by the scarcity of antigens specific to the tumour plasma cells. Most candidate targets are shared by healthy tissues, and entail high risks of toxicity. Therefore several strategies have been proposed to regulate CAR-T-cell function as well as to enhance CAR-T-cell specificity against tumour cells. In this article we summarize the surface markers that have been investigated as targets to eliminate MM plasma cells and the MM-specific CARs that have been developed to date. Then we describe the different CAR-T-cell designs that could be applied in the case of MM to circumvent current problems of toxicity.
Extrathymic T cell precursors can be detected in many tissues and represent an immediately competent population for rapid T cell reconstitution in the event of immunodeficiencies. Blood T cell progenitors have been detected, but their source in the bone marrow (BM) remains unclear. Prospective purification of BM-resident and circulating progenitors, together with RT-PCR single-cell analysis, was used to evaluate and compare multipotent progenitors (MPPs) and common lymphoid progenitors (CLPs). Molecular analysis of circulating progenitors in comparison with BM-resident progenitors revealed that CCR9+ progenitors are more abundant in the blood than CCR7+ progenitors. Second, although Flt3− CLPs are less common in the BM, they are abundant in the blood and have reduced Cd25+-expressing cells and downregulated c-Kit and IL-7Rα intensities. Third, in contrast, stage 3 MPP (MPP3) cells, the unique circulating MPP subset, have upregulated Il7r, Gata3, and Notch1 in comparison with BM-resident counterparts. Evaluation of the populations’ respective abilities to generate splenic T cell precursors (Lin−Thy1.2+CD25+IL7Rα+) after grafting recipient nude mice revealed that MPP3 cells were the most effective subset (relative to CLPs). Although several lymphoid genes are expressed by MPP3 cells and Flt3− CLPs, the latter only give rise to B cells in the spleen, and Notch1 expression level is not modulated in the blood, as for MPP3 cells. We conclude that CLPs have reached the point where they cannot be a Notch1 target, a limiting condition on the path to T cell engagement.
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