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Environmental challenges to epithelial cells trigger gene expression changes that elicit context-appropriate immune responses. We found that the chromatin remodeler Mi-2β controls epidermal homeostasis by regulating the genes involved in keratinocyte and immune-cell activation to maintain an inactive state. Mi-2β depletion resulted in rapid deployment of both a pro-inflammatory and an immunosuppressive response in the skin. A key target of Mi-2β in keratinocytes is the pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP). Loss of TSLP receptor (TSLPR) signaling specifically in regulatory T (Treg) cells prevented their activation and permitted rapid progression from a skin pro-inflammatory response to a lethal systemic condition. Thus, in addition to their well-characterized role in pro-inflammatory responses, keratinocytes also directly support immune-suppressive responses that are critical for re-establishing organismal homeostasis.

The cytokine TSLP has been shown to be a key factor in maintaining immune homeostasis and regulating inflammatory responses at mucosal barriers. While the role of TSLP in type 2 immune responses has been investigated extensively, recent studies have found an expanding role for TSLP in inflammatory diseases and cancer. In this Review, we will highlight major recent advances in TSLP biology, along with results from emerging clinical trials of anti-TSLP agents used for the treatment of a variety of inflammatory conditions.

Summary Inflammation induced during infection can both promote and suppress immunity. This contradiction suggests that inflammatory cytokines impact the immune system in a context-dependent manner. Here we show that non-specific bystander inflammation conditioned naïve CD4+ T cells for enhanced peripheral Foxp3 induction and reduced effector differentiation. This resulted in inhibition of immune responses in vivo via Foxp3-dependent effect on antigen-specific naïve CD4+ T cell precursors. Such conditioning may have evolved to allow immunity to infection while limiting subsequent autoimmunity caused by release of self-antigens in the wake of infection. Furthermore, this phenomenon suggests a mechanistic explanation for the concept that early tuning of the immune system by infection impacts the long-term quality of immune regulation.

Tumors actively manipulate the immune response through the production of factors that attract immune cells and subsequently alter their ability to recognize and effectively remove the tumor. While this mechanism for evading the immune system is an important aspect of tumor survival, the factors that serve as primary growth factors for the tumor are less understood. Here we demonstrate a previously unknown mechanism by which breast-cancer cells manipulate tumor-infiltrating myeloid cells to maintain their survival. Tumor-derived interleukin 1α (IL-1α), acting on infiltrating myeloid cells, induced the expression of a critical tumor survival factor, the cytokine TSLP. TSLP promoted the survival of the tumor cells through induction of the expression of the anti-apoptotic molecule Bcl-2. TSLP signaling was also required for metastasis to the lungs. These studies define a novel IL-1α-TSLP-mediated crosstalk between tumor-infiltrating myeloid cells and tumor cells in the control of metastatic breast cancer.

The Greek island of Crete became host to lively discussions on immunoregulation as experts from around the world gathered for the 7th Aegean Conference on Autoimmunity in September 2015.

In the version of this article initially published, the far right label along the horizontal axis of the right plot of Fig. 1e (4T1-Tslp-/- 4-6), the middle and right labels along the horizontal axis of the far right plot of Fig. 3d (4T1-Tslpr-/- 4-6 and 4T1-Tslpr-/- 2-3, respectively), and the far right label along the horizontal axis of Fig. 6h (4T1-Tslpr-/- 2-3) were incorrect. The correct labels are as follows: Fig. 1e, 4T1-Tslpr-/- 4-6; Fig. 3d, 4T1-Tslp-/- 2-3 and 4T1-Tslpr-/- 4-6, respectively; and Fig. 6h, 4T1-Tslpr-/- 4-6. Also, Fig. 4e was incorrectly a duplicate of an adjacent panel. The errors have been corrected in the HTML and PDF version of the article.

Thymic stromal lymphopoietin (TSLP) is an interleukin 7 (IL-7)-like cytokine originally characterized by its ability to promote the activation of B cells and dendritic cells (DCs). Subsequent studies have shown that TSLP promotes T helper type 2 (TH2) cell responses associated with immunity to some helminth parasites and the pathogenesis of many inflammatory diseases, including atopic dermatitis and asthma. This review will focus on recent findings indicating that in addition to influencing B cell and DC function, TSLP can promote TH2 cytokine–associated inflammation by directly promoting the effector functions of CD4+ TH2 cells, basophils and other granulocyte populations while simultaneously limiting the expression of DC-derived proinflammatory cytokines and promoting regulatory T cell responses in peripheral tissues.

The cytokine thymic stromal lymphopoietin (TSLP) drives immature B cell development in vitro and may regulate T helper type 2 responses. Here we analyzed the involvement of TSLP in B cell development in vivo with a doxycycline-inducible, keratin 5-driven transgene encoding TSLP (K5-TSLP). K5-TSLP-transgenic mice given doxycycline showed an influx of immature B cells into the periphery, with population expansion of follicular mature B cells, near-complete loss of marginal zone and marginal zone precursor B cells, and 'preferential' population expansion of peritoneal B-1b B cells. These changes promoted cryoglobulin production and immune complex-mediated renal disease. Identical events occurred in mice without T cells, in alternative TSLP-transgenic models and in K5-TSLP-transgenic mice with undetectable systemic TSLP. These observations suggest that signals mediating localized TSLP expression may modulate systemic B cell development and promote humoral autoimmunity.

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.

Medullary thymic epithelial cells (mTECs) are critical in establishing and maintaining the appropriate microenvironment for negative selection and maturation of immunocompetent T cells with a self-tolerant T cell antigen receptor repertoire. Cues that direct proliferation and maturation of mTECs are provided by members of the tumor necrosis factor (TNF) superfamily expressed on developing thymocytes. Here we demonstrate a negative role of the morphogen TGF-β in tempering these signals under physiological conditions, limiting both growth and function of the thymic medulla. Eliminating TGF-β signaling specifically in TECs or by pharmacological means increased the size of the mTEC compartment, enhanced negative selection and functional maturation of medullary thymocytes as well as the production of regulatory T cells, thus reducing the autoreactive potential of peripheral T cells. © 2014 Nature America, Inc.

Signaling by type I cytokines involves the formation of receptor homodimers, heterodimers or higher order receptor oligomers. Here we report the cloning of a type I cytokine receptor subunit that is most closely related to the common cytokine receptor gamma chain (gamma c). Binding and crosslinking experiments demonstrate that this protein is the receptor for a recently described interleukin 7 (IL-7)-like factor, thymic stromal lymphopoietin (TSLP). Binding of TSLP to the thymic stromal lymphopoietin receptor (TSLPR) is increased markedly in the presence of the IL-7 receptor alpha chain (IL-7R alpha). IL-7R alpha-expressing but not parental 32D cells proliferate in the presence of exogenous TSLP. Moreover, a combination of IL-7R alpha and TSLPR is required for TSLP-dependent activation of a STAT5-dependent reporter construct. Thus it is shown that IL-7R alpha is a component of both the IL-7 and TSLP receptors, which helps to explain why deletion of the gene that encodes IL-7R alpha affects the lymphoid system more severely than deletion of the gene encoding IL-7 does. Cloning of TSLPR should facilitate an understanding of TSLP function and its signaling mechanism.

Dendritic cells (DCs) are critical in immune responses, linking innate and adaptive immunity. We found here that DC-specific deletion of the transcription factor STAT5 was not critical for development but was required for T helper type 2 (TH2), but not TH1, allergic responses in both the skin and lungs. Loss of STAT5 in DCs led to the inability to respond to thymic stromal lymphopoietin (TSLP). STAT5 was required for TSLP-dependent DC activation, including upregulation of the expression of costimulatory molecules and chemokine production. Furthermore, TH2 responses in mice with DC-specific loss of STAT5 resembled those seen in mice deficient in the receptor for TSLP. Our results show that the TSLP-STAT5 axis in DCs is a critical component for the promotion of type 2 immunity at barrier surfaces.

Thymic stromal lymphopoietin, a four helix–bundle cytokine, is expressed mainly by barrier epithelial cells and is a potent activator of several cell types, particularly myeloid dendritic cells. TSLP influences the outcome of interactions between dendritic cells and CD4+ thymocytes and T cells in many situations, such as the regulation of the positive selection of regulatory T cells, maintenance of peripheral CD4+ T cell homeostasis and induction of CD4+ T cell–mediated allergic inflammation.

Nat. Immunol. 14, 364–371 (2013); published online 24 February 2013; corrected after print 23 September 2013 In the version of this article initially published, author Daniel H. Kaplan was not included. The correct list of authors and affiliations is as follows: Bryan D Bell1,2,7, Masayuki Kitajima1,2,7, Ryan P Larson1,2, Thomas A Stoklasek1,2, Kristen Dang1, Kazuhito Sakamoto3, Kay-Uwe Wagner3, Daniel H Kaplan4, Boris Reizis5, Lothar Hennighausen6 & Steven F Ziegler1,2