Epidermal {gamma}{delta} T cells originate from yolk sac hematopoiesis and clonally self-renew in the adult
The murine epidermis harbors two immune cell lineages, Langerhans cells (LCs) and T cells known as dendritic epidermal T cells (DETCs). LCs develop from both early yolk sac (YS) progenitors and fetal liver monocytes before locally self-renewing in the adult. For DETCs, the mechanisms of homeostatic maintenance and their hematopoietic origin are largely unknown. Here, we exploited multicolor fate mapping systems to reveal that DETCs slowly turn over at steady state. Like for LCs, homeostatic maintenance of DETCs is achieved by clonal expansion of tissue-resident cells assembled in proliferative units. The same mechanism, al...
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Gentek, R., Ghigo, C., Hoeffel, G., Jorquera, A., Msallam, R., Wienert, S., Klauschen, F., Ginhoux, F., Bajenoff, M. Tags: Innate Immunity and Inflammation, Hematopoiesis Brief Definitive Reports Source Type: research

Endothelial cells act as gatekeepers for LT{beta}R-dependent thymocyte emigration
The emigration of mature thymocytes from the thymus is critical for establishing peripheral T cell compartments. However, the pathways controlling this process and the timing of egress in relation to postselection developmental stages are poorly defined. Here, we reexamine thymocyte egress and test current and opposing models in relation to the requirement for LTβR, a regulator of thymic microenvironments and thymocyte emigration. Using cell-specific gene targeting, we show that the requirement for LTβR in thymocyte egress is distinct from its control of thymic epithelium and instead maps to expression by endothe...
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: James, K. D., Cosway, E. J., Lucas, B., White, A. J., Parnell, S. M., Carvalho-Gaspar, M., Tumanov, A. V., Anderson, G., Jenkinson, W. E. Tags: Brief Definitive Reports Source Type: research

The conduit system exports locally secreted IgM from lymph nodes
Immunoglobulin M (IgM) is the first type of antibody produced during acute infections and thus provides an early line of specific defense against pathogens. Being produced in secondary lymphoid organs, IgM must rapidly be exported to the blood circulation. However, it is currently unknown how such large pentameric molecules are released from lymph nodes (LNs). Here, we show that upon immunization, IgM transiently gains access to the luminal side of the conduit system, a reticular infrastructure enabling fast delivery of tissue-derived soluble substances to the LN parenchyma. Using microinjections of purified IgM, we demons...
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Thierry, G. R., Kuka, M., De Giovanni, M., Mondor, I., Brouilly, N., Iannacone, M., Bajenoff, M. Tags: Brief Definitive Reports Source Type: research

Sensing danger through a "finger"
In this issue of JEM, the study by Chen et al. (https://doi.org/10.1084/jem.20181031) reveals a previously unrecognized role of cellular nucleic acid–binding protein (Cnbp) as a novel transcriptional regulator of interleukin-12β (IL-12β) transcription and IL-12–driven, Th1-mediated immune responses, which has important implications for both host defense and inflammatory disease. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Ma, X. Tags: Insights Source Type: research

Deciphering cancer fibroblasts
In this issue of JEM, Raz et al. (https://doi.org/10.1084/jem.20180818) identify a subset of bone marrow–derived cells that uniquely promotes breast cancer angiogenesis and tumor growth. The existence of functional heterogeneity among stromal populations motivates further fundamental and therapeutic inquiries. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Biffi, G., Tuveson, D. A. Tags: Insights Source Type: research

TLR8: No gain, no pain
TLRs have been well characterized in the context of immunity, although TLR8 is understudied due to its controversial function in mice. In this issue of JEM, the new work by Zhang et al. (https://doi.org/10.1084/jem.20180800) demonstrates that TLR8 activated by miR-21 controls neuropathic pain using a non-MyD88–dependent pathway. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Barrat, F. J. Tags: Neuroinflammation, Innate Immunity and Inflammation, Neuroscience Insights Source Type: research

{gamma}{delta} T cells: A disappearing act with a big reveal
In this issue of JEM, Sandrock et al. (https://doi.org/10.1084/jem.20181439) compare the origin of IL-17–producing T cells (T17) with other T cell populations and demonstrate the role T17 cells play in skin pathology. Using two genetically modified mouse models, one with inducible T cell–specific labeling and the other with conditional T cell depletion, the authors find that T17 are mostly long-lived lymphocytes and that depleting T cells protects mice from psoriasis. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Jameson, J. M. Tags: Insights Source Type: research

IgMs exit route
In this issue of JEM, Thierry et al. (https://doi.org/10.1084/jem.20180344) demonstrate that, once secreted by freshly activated plasmablasts, IgM leaves the lymph node via the microarchitecture of the fibroblastic reticular cell conduit. This work demonstrates how the very peculiar stromal compartment of lymphatic organs optimizes the systemic distribution of immune effectors. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Reversat, A., Sixt, M. Tags: Insights Source Type: research

Peyers patch myeloid cells infection by Listeria signals through gp38+ stromal cells and locks intestinal villus invasion
This study unveils a novel innate immune response to an enteropathogen, which implicates gp38+ stromal cells and locks intestinal villus invasion, but favors colitis. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - November 5, 2018 Category: Internal Medicine Authors: Disson, O., Bleriot, C., Jacob, J.-M., Serafini, N., Dulauroy, S., Jouvion, G., Fevre, C., Gessain, G., Thouvenot, P., Eberl, G., Di Santo, J. P., Peduto, L., Lecuit, M. Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense, Mucosal Immunology Articles Source Type: research

Mycobacterium tuberculosis-induced IFN-{beta} production requires cytosolic DNA and RNA sensing pathways
RNA sensing pathways are key elements in a host immune response to viral pathogens, but little is known of their importance during bacterial infections. We found that Mycobacterium tuberculosis (M.tb) actively releases RNA into the macrophage cytosol using the mycobacterial SecA2 and ESX-1 secretion systems. The cytosolic M.tb RNA induces IFN-β production through the host RIG-I/MAVS/IRF7 RNA sensing pathway. The inducible expression of IRF7 within infected cells requires an autocrine signaling through IFN-β and its receptor, and this early IFN-β production is dependent on STING and IRF3 activation. M.tb infe...
Source: The Journal of Experimental Medicine - November 5, 2018 Category: Internal Medicine Authors: Cheng, Y., Schorey, J. S. Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense Articles Source Type: research

Macrophage-specific MHCII expression is regulated by a remote Ciita enhancer controlled by NFAT5
MHCII in antigen-presenting cells (APCs) is a key regulator of adaptive immune responses. Expression of MHCII genes is controlled by the transcription coactivator CIITA, itself regulated through cell type–specific promoters. Here we show that the transcription factor NFAT5 is needed for expression of Ciita and MHCII in macrophages, but not in dendritic cells and other APCs. NFAT5-deficient macrophages showed defective activation of MHCII-dependent responses in CD4+ T lymphocytes and attenuated capacity to elicit graft rejection in vivo. Ultrasequencing analysis of NFAT5-immunoprecipitated chromatin uncovered an NFAT5...
Source: The Journal of Experimental Medicine - November 5, 2018 Category: Internal Medicine Authors: Buxade, M., Huerga Encabo, H., Riera-Borrull, M., Quintana-Gallardo, L., Lopez-Cotarelo, P., Tellechea, M., Martinez-Martinez, S., Redondo, J. M., Martin-Caballero, J., Flores, J. M., Bosch, E., Rodriguez-Fernandez, J. L., Aramburu, J., Lopez-Rodriguez, C Tags: Innate Immunity and Inflammation Articles Source Type: research

SOX4 controls invariant NKT cell differentiation by tuning TCR signaling
Natural killer T (NKT) cells expressing the invariant T cell receptor (iTCR) serve an essential function in clearance of certain pathogens and have been implicated in autoimmune and allergic diseases. Complex effector programs of these iNKT cells are wired in the thymus, and upon thymic egress, they can respond within hours of antigenic challenges, classifying iNKT cells as innate-like. It has been assumed that the successful rearrangement of the invariant iTCRα chain is the central event in the divergence of immature thymocytes to the NKT cell lineage, but molecular properties that render the iTCR signaling distinct...
Source: The Journal of Experimental Medicine - November 5, 2018 Category: Internal Medicine Authors: Malhotra, N., Qi, Y., Spidale, N. A., Frascoli, M., Miu, B., Cho, O., Sylvia, K., Kang, J. Tags: Hematopoiesis Articles Source Type: research

ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS-STING
A coding variant of the inflammatory bowel disease (IBD) risk gene ATG16L1 has been associated with defective autophagy and deregulation of endoplasmic reticulum (ER) function. IL-22 is a barrier protective cytokine by inducing regeneration and antimicrobial responses in the intestinal mucosa. We show that ATG16L1 critically orchestrates IL-22 signaling in the intestinal epithelium. IL-22 stimulation physiologically leads to transient ER stress and subsequent activation of STING-dependent type I interferon (IFN-I) signaling, which is augmented in Atg16l1IEC intestinal organoids. IFN-I signals amplify epithelial TNF product...
Source: The Journal of Experimental Medicine - November 5, 2018 Category: Internal Medicine Authors: Aden, K., Tran, F., Ito, G., Sheibani-Tezerji, R., Lipinski, S., Kuiper, J. W., Tschurtschenthaler, M., Saveljeva, S., Bhattacharyya, J., Häsler, R., Bartsch, K., Luzius, A., Jentzsch, M., Falk-Paulsen, M., Stengel, S. T., Welz, L., Schwarzer, R., Tags: Innate Immunity and Inflammation, Mucosal Immunology Articles Source Type: research

USP38 critically promotes asthmatic pathogenesis by stabilizing JunB protein
Th2 immune response is critical for allergic asthma pathogenesis. Molecular mechanisms for regulating Th2 immunity are still not well understood. Here we report that the ubiquitin-specific protease USP38 is crucial for Th2-mediated allergic asthma. TCR stimulation up-regulated the USP38 level, and USP38 in turn mediated the protein stabilization of JunB, a transcription factor specific for Th2 development. Consequently, USP38 was specifically required for TCR-induced production of Th2 cytokines and Th2 development both in vitro and in vivo, and USP38-deficient mice were resistant to asthma pathogenesis induced by OVA or HD...
Source: The Journal of Experimental Medicine - November 5, 2018 Category: Internal Medicine Authors: Chen, S., Yun, F., Yao, Y., Cao, M., Zhang, Y., Wang, J., Song, X., Qian, Y. Tags: Articles Source Type: research

KDM4B-regulated unfolded protein response as a therapeutic vulnerability in PTEN-deficient breast cancer
PTEN deficiency in breast cancer leads to resistance to PI3K–AKT inhibitor treatment despite aberrant activation of this signaling pathway. Here, we report that genetic depletion or small molecule inhibition of KDM4B histone demethylase activates the unfolded protein response (UPR) pathway and results in preferential apoptosis in PTEN-deficient triple-negative breast cancers (TNBCs). Intriguingly, this function of KDM4B on UPR requires its demethylase activity but is independent of its canonical role in histone modification, and acts through its cytoplasmic interaction with eIF2α, a crucial component of UPR sig...
Source: The Journal of Experimental Medicine - November 5, 2018 Category: Internal Medicine Authors: Wang, W., Oguz, G., Lee, P. L., Bao, Y., Wang, P., Terp, M. G., Ditzel, H. J., Yu, Q. Tags: Solid Tumors Articles Source Type: research