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The ubiquitin-editing enzyme A20 controls NK cell homeostasis through regulation of mTOR activity and TNF
This study therefore maps A20 as a crucial regulator of mTOR signaling and underscores the need for a tightly balanced mTOR pathway in NK cell homeostasis. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Vetters, J., van Helden, M. J., Wahlen, S., Tavernier, S. J., Martens, A., Fayazpour, F., Vergote, K., Vanheerswynghels, M., Deswarte, K., Van Moorleghem, J., De Prijck, S., Takahashi, N., Vandenabeele, P., Boon, L., van Loo, G., Vivier, E., Lambrecht, B. Tags: Innate Immunity and Inflammation Brief Definitive Reports Source Type: research

A stromal cell niche sustains ILC2-mediated type-2 conditioning in adipose tissue
Group-2 innate lymphoid cells (ILC2), type-2 cytokines, and eosinophils have all been implicated in sustaining adipose tissue homeostasis. However, the interplay between the stroma and adipose-resident immune cells is less well understood. We identify that white adipose tissue–resident multipotent stromal cells (WAT-MSCs) can act as a reservoir for IL-33, especially after cell stress, but also provide additional signals for sustaining ILC2. Indeed, we demonstrate that WAT-MSCs also support ICAM-1–mediated proliferation and activation of LFA-1–expressing ILC2s. Consequently, ILC2-derived IL-4 and IL-13 fee...
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Rana, B. M. J., Jou, E., Barlow, J. L., Rodriguez-Rodriguez, N., Walker, J. A., Knox, C., Jolin, H. E., Hardman, C. S., Sivasubramaniam, M., Szeto, A., Cohen, E. S., Scott, I. C., Sleeman, M. A., Chidomere, C. I., Cruz Migoni, S., Caamano, J., Jorgensen, Tags: Brief Definitive Reports Source Type: research

Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses
This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in IL6ST, STAT3, and ZNF341, genes encoding different components of the IL-6 signaling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Spencer, S., Köstel Bal, S., Egner, W., Lango Allen, H., Raza, S. I., Ma, C. A., Gürel, M., Zhang, Y., Sun, G., Sabroe, R. A., Greene, D., Rae, W., Shahin, T., Kania, K., Ardy, R. C., Thian, M., Staples, E., Pecchia-Bekkum, A., Worrall, W. Tags: Immunodeficiency Brief Definitive Reports Source Type: research

A pathogenic role of plasmacytoid dendritic cells in autoimmunity and chronic viral infection
Following the discovery of plasmacytoid dendritic cells (pDCs) and of their extraordinary ability to produce type I IFNs (IFN-I) in response to TLR7 and TLR9 stimulation, it is assumed that their main function is to participate in the antiviral response. There is increasing evidence suggesting that pDCs and/or IFN-I can also have a detrimental role in a number of inflammatory and autoimmune diseases, in the context of chronic viral infections and in cancers. Whether these cells should be targeted in patients and how much of their biology is connected to IFN-I production remains unclear and is discussed here. (Source: The J...
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Barrat, F. J., Su, L. Tags: Autoimmunity, Innate Immunity and Inflammation, Infectious Disease and Host Defense Review Source Type: research

Ross Levine: Focus on the critical questions
Ross Levine is a physician-scientist at Memorial Sloan Kettering Cancer Center in New York, where his laboratory studies the genetic basis of myeloid malignancies. Work from Ross’ laboratory has shown how mutations in the JAK–STAT pathway and epigenetic regulators play a role in myeloproliferative neoplasms, and JAK inhibitors are now successfully used to treat myeloproliferative neoplasms. We spoke to Ross about his journey in science so far. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Houston, S. Tags: People & amp; Ideas Source Type: research

ILC2s chew the fat
In this issue of JEM, Rana et al. (https://doi.org/10.1084/jem.20190689) report that adipose tissue multipotent stromal cells (MSCs) provide multifaceted support for adipose tissue–resident ILC2s through contact-mediated proliferation and IL-33–mediated stress-induced activation. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Ricardo-Gonzalez, R. R., Locksley, R. M. Tags: Innate Immunity and Inflammation Insights Source Type: research

The nature of human IL-6
Countless functions have been attributed experimentally to IL-6. In this issue of JEM, Spencer et al. (https://doi.org/10.1084/jem.20190344) reveal essential, nonredundant functions of human IL-6. Patients with genetic deficiencies of the IL-6 receptor suffer from "hyper IgE syndrome." (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Puel, A., Casanova, J.-L. Tags: Immunodeficiency, Infectious Disease and Host Defense, Human Disease Genetics Insights Source Type: research

Correction: CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets
Vol. 211, No. 1, January 13, 2014. 10.1084/jem.20131142. The authors regret that in the original version of Fig. 3 A, the axes labels in the flow cytometry plots were incorrect. The revised panel appears below... (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Smigiel, K. S., Richards, E., Srivastava, S., Thomas, K. R., Dudda, J. C., Klonowski, K. D., Campbell, D. J. Tags: Corrections Source Type: research

Krüppel-like factor 3 inhibition by mutated lncRNA Reg1cp results in human high bone mass syndrome
High bone mass (HBM) is usually caused by gene mutations, and its mechanism remains unclear. In the present study, we identified a novel mutation in the long noncoding RNA Reg1cp that is associated with HBM. Subsequent analysis in 1,465 Chinese subjects revealed that heterozygous Reg1cp individuals had higher bone density compared with subjects with WT Reg1cp. Mutant Reg1cp increased the formation of the CD31hiEmcnhi endothelium in the bone marrow, which stimulated angiogenesis during osteogenesis. Mechanistically, mutant Reg1cp directly binds to Krüppel-like factor 3 (KLF3) to inhibit its activity. Mice depleted o...
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Yang, M., Guo, Q., Peng, H., Xiao, Y.-Z., Xiao, Y., Huang, Y., Li, C.-J., Su, T., Zhang, Y.-L., Lei, M.-X., Chen, H.-L., Jiang, T.-J., Luo, X.-H. Tags: Metabolism Articles Source Type: research

C3- and CR3-dependent microglial clearance protects photoreceptors in retinitis pigmentosa
Complement activation has been implicated as contributing to neurodegeneration in retinal and brain pathologies, but its role in retinitis pigmentosa (RP), an inherited and largely incurable photoreceptor degenerative disease, is unclear. We found that multiple complement components were markedly up-regulated in retinas with human RP and the rd10 mouse model, coinciding spatiotemporally with photoreceptor degeneration, with increased C3 expression and activation localizing to activated retinal microglia. Genetic ablation of C3 accelerated structural and functional photoreceptor degeneration and altered retinal inflammatory...
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Silverman, S. M., Ma, W., Wang, X., Zhao, L., Wong, W. T. Tags: Neuroinflammation, Innate Immunity and Inflammation, Neuroscience Articles Source Type: research

Cartilage-binding antibodies induce pain through immune complex-mediated activation of neurons
Rheumatoid arthritis–associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody–induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest tha...
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Bersellini Farinotti, A., Wigerblad, G., Nascimento, D., Bas, D. B., Morado Urbina, C., Nandakumar, K. S., Sandor, K., Xu, B., Abdelmoaty, S., Hunt, M. A., Ängeby Möller, K., Baharpoor, A., Sinclair, J., Jardemark, K., Lanner, J. T., Khmal Tags: Autoimmunity, Innate Immunity and Inflammation, Neuroscience Articles Source Type: research

The intracellular domain of CX3CL1 regulates adult neurogenesis and Alzheimers amyloid pathology
This study demonstrates a novel function that CX3CL1 exerts. CX3CL1 is sequentially cleaved by α-, β-, and -secretase, and the released CX3CL1 intracellular domain (CX3CL1-ICD) would translocate into the cell nucleus to alter gene expression due to this back-signaling function. Amyloid deposition and neuronal loss were significantly reduced when membrane-anchored CX3CL1 C-terminal fragment (CX3CL1-ct) was overexpressed in Alzheimer’s 5xFAD mouse model. The reversal of neuronal loss in 5xFAD can be attributed to increased neurogenesis by CX3CL1-ICD, as revealed by morphological and unbiased RNA-sequencing a...
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Fan, Q., Gayen, M., Singh, N., Gao, F., He, W., Hu, X., Tsai, L.-H., Yan, R. Tags: Neuroscience Articles Source Type: research

Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium
To define the role of ERK1/2 signaling in the quiescent endothelium, we induced endothelial Erk2 knockout in adult Erk1–/– mice. This resulted in a rapid onset of hypertension, a decrease in eNOS expression, and an increase in endothelin-1 plasma levels, with all mice dying within 5 wk. Immunostaining and endothelial fate mapping showed a robust increase in TGFβ signaling leading to widespread endothelial-to-mesenchymal transition (EndMT). Fibrosis affecting the cardiac conduction system was responsible for the universal lethality in these mice. Other findings included renal endotheliosis, loss of fenestra...
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Ricard, N., Scott, R. P., Booth, C. J., Velazquez, H., Cilfone, N. A., Baylon, J. L., Gulcher, J. R., Quaggin, S. E., Chittenden, T. W., Simons, M. Tags: Cardiovascular Biology Articles Source Type: research

The adjuvant GLA-SE promotes human Tfh cell expansion and emergence of public TCR{beta} clonotypes
The generation of protective humoral immunity after vaccination relies on the productive interaction between antigen-specific B cells and T follicular helper (Tfh) cells. Despite the central role of Tfh cells in vaccine responses, there is currently no validated way to enhance their differentiation in humans. From paired human lymph node and blood samples, we identify a population of circulating Tfh cells that are transcriptionally and clonally similar to germinal center Tfh cells. In a clinical trial of vaccine formulations, circulating Tfh cells were expanded in Tanzanian volunteers when an experimental malaria vaccine w...
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Hill, D. L., Pierson, W., Bolland, D. J., Mkindi, C., Carr, E. J., Wang, J., Houard, S., Wingett, S. W., Audran, R., Wallin, E. F., Jongo, S. A., Kamaka, K., Zand, M., Spertini, F., Daubenberger, C., Corcoran, A. E., Linterman, M. A. Tags: Infectious Disease and Host Defense Articles Source Type: research

Regulatory roles of IL-10-producing human follicular T cells
Mucosal lymphoid tissues such as human tonsil are colonized by bacteria and exposed to ingested and inhaled antigens, requiring tight regulation of immune responses. Antibody responses are regulated by follicular helper T (TFH) cells and FOXP3+ follicular regulatory T (TFR) cells. Here we describe a subset of human tonsillar follicular T cells identified by expression of TFH markers and CD25 that are the main source of follicular T (TF) cell–derived IL-10. Despite lack of FOXP3 expression, CD25+ TF cells resemble T reg cells in high CTLA4 expression, low IL-2 production, and their ability to repress T cell proliferat...
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Canete, P. F., Sweet, R. A., Gonzalez-Figueroa, P., Papa, I., Ohkura, N., Bolton, H., Roco, J. A., Cuenca, M., Bassett, K. J., Sayin, I., Barry, E., Lopez, A., Canaday, D. H., Meyer-Hermann, M., Doglioni, C., Fazekas de St Groth, B., Sakaguchi, S., Cook, Tags: Articles Source Type: research