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IL2RB maintains immune harmony
How the IL-2 receptor β-chain specifically shapes immunity has remained enigmatic. In this issue of JEM, Zhang et al. (https://doi.org/10.1084/jem.20182304) and Fernandez et al. (https://doi.org/10.1084/jem.20182015) independently report the first observations of autosomal recessive mutations in IL2RB, revealing a requirement for IL2RB in immunity and peripheral immune tolerance. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Campbell, T. M., Bryceson, Y. T. Tags: Autoimmunity, Immunodeficiency, Infectious Disease and Host Defense, Human Disease Genetics Insights Source Type: research

Correction: Use of extracellular vesicles from lymphatic drainage as surrogate markers of melanoma progression and BRAFV600E mutation
Vol. 216, No. 5, May 6, 2019. 10.1084/jem.20181522. The authors regret that in the original version of their paper, Laura Santambrogio and Mary Sue Brady were inadvertently omitted from the author list. The corrected author list appears... (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Garcia-Silva, S., Benito-Martin, A., Sanchez-Redondo, S., Hernandez-Barranco, A., Ximenez-Embun, P., Nogues, L., Mazariegos, M. S., Brinkmann, K., Lopez, A. A., Meyer, L., Rodriguez, C., Garcia-Martin, C., Boskovic, J., Leton, R., Montero, C., Robledo, M. Tags: Corrections Source Type: research

CD4+ resident memory T cells dominate immunosurveillance and orchestrate local recall responses
This study examines the extent to which memory CD4+ T cells share immunosurveillance strategies with CD8+ resident memory T cells (TRM). After acute viral infection, memory CD4+ T cells predominantly used residence to survey nonlymphoid tissues, albeit not as stringently as observed for CD8+ T cells. In contrast, memory CD4+ T cells were more likely to be resident within lymphoid organs than CD8+ T cells. Migration properties of memory-phenotype CD4+ T cells in non-SPF parabionts were similar, generalizing these results to diverse infections and conditions. CD4+ and CD8+ TRM shared overlapping transcriptional signatures an...
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Beura, L. K., Fares-Frederickson, N. J., Steinert, E. M., Scott, M. C., Thompson, E. A., Fraser, K. A., Schenkel, J. M., Vezys, V., Masopust, D. Tags: Mucosal Immunology Articles Source Type: research

Bloom syndrome protein restrains innate immune sensing of micronuclei by cGAS
Cellular innate immune sensors of DNA are essential for host defense against invading pathogens. However, the presence of self-DNA inside cells poses a risk of triggering unchecked immune responses. The mechanisms limiting induction of inflammation by self-DNA are poorly understood. BLM RecQ–like helicase is essential for genome integrity and is deficient in Bloom syndrome (BS), a rare genetic disease characterized by genome instability, accumulation of micronuclei, susceptibility to cancer, and immunodeficiency. Here, we show that BLM-deficient fibroblasts show constitutive up-regulation of inflammatory interferon-s...
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Gratia, M., Rodero, M. P., Conrad, C., Bou Samra, E., Maurin, M., Rice, G. I., Duffy, D., Revy, P., Petit, F., Dale, R. C., Crow, Y. J., Amor-Gueret, M., Manel, N. Tags: Innate Immunity and Inflammation, Human Disease Genetics, Genome Stability Articles Source Type: research

Thyrotropin aggravates atherosclerosis by promoting macrophage inflammation in plaques
Subclinical hypothyroidism is associated with cardiovascular diseases, yet the underlying mechanism remains largely unknown. Herein, in a common population (n = 1,103), TSH level was found to be independently correlated with both carotid plaque prevalence and intima-media thickness. Consistently, TSH receptor ablation in ApoE–/– mice attenuated atherogenesis, accompanied by decreased vascular inflammation and macrophage burden in atherosclerotic plaques. These results were also observed in myeloid-specific Tshr-deficient ApoE–/– mice, which indicated macrophages to be a critical target of the proinf...
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Yang, C., Lu, M., Chen, W., He, Z., Hou, X., Feng, M., Zhang, H., Bo, T., Zhou, X., Yu, Y., Zhang, H., Zhao, M., Wang, L., Yu, C., Gao, L., Jiang, W., Zhang, Q., Zhao, J. Tags: Cardiovascular Biology, Innate Immunity and Inflammation Articles Source Type: research

CCL22 controls immunity by promoting regulatory T cell communication with dendritic cells in lymph nodes
In conclusion, we identify the CCL22–CCR4 axis as an immune checkpoint that is crucial for the control of T cell immunity. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Rapp, M., Wintergerst, M. W. M., Kunz, W. G., Vetter, V. K., Knott, M. M. L., Lisowski, D., Haubner, S., Moder, S., Thaler, R., Eiber, S., Meyer, B., Röhrle, N., Piseddu, I., Grassmann, S., Layritz, P., Kühnemuth, B., Stutte, S., Bourquin, Tags: Autoimmunity, Tumor Immunology Articles Source Type: research

Longitudinal profiling of human blood transcriptome in healthy and lupus pregnancy
Systemic lupus erythematosus carries an increased risk of pregnancy complications, including preeclampsia and fetal adverse outcomes. To identify the underlying molecular mechanisms, we longitudinally profiled the blood transcriptome of 92 lupus patients and 43 healthy women during pregnancy and postpartum and performed multicolor flow cytometry in a subset of them. We also profiled 25 healthy women undergoing assisted reproductive technology to monitor transcriptional changes around embryo implantation. Sustained down-regulation of multiple immune signatures, including interferon and plasma cells, was observed during heal...
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Hong, S., Banchereau, R., Maslow, B.-S. L., Guerra, M. M., Cardenas, J., Baisch, J., Branch, D. W., Porter, T. F., Sawitzke, A., Laskin, C. A., Buyon, J. P., Merrill, J., Sammaritano, L. R., Petri, M., Gatewood, E., Cepika, A.-M., Ohouo, M., Obermoser, G. Tags: Autoimmunity, Innate Immunity and Inflammation, Tolerance Articles Source Type: research

Active PI3K abrogates central tolerance in high-avidity autoreactive B cells
Autoreactive B cells that bind self-antigen with high avidity in the bone marrow undergo mechanisms of central tolerance that prevent their entry into the peripheral B cell population. These mechanisms are breached in many autoimmune patients, increasing their risk of B cell–mediated autoimmune diseases. Resolving the molecular pathways that can break central B cell tolerance could therefore provide avenues to diminish autoimmunity. Here, we show that B cell–intrinsic expression of a constitutively active form of PI3K-P110α by high-avidity autoreactive B cells of mice completely abrogates central B cell t...
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Greaves, S. A., Peterson, J. N., Strauch, P., Torres, R. M., Pelanda, R. Tags: Tolerance Articles Source Type: research

PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma
Glioblastoma (GBM) is the most malignant brain tumor with profound genomic alterations. Tumor suppressor genes regulate multiple signaling networks that restrict cellular proliferation and present barriers to malignant transformation. While bona fide tumor suppressors such as PTEN and TP53 often undergo inactivation due to mutations, there are several genes for which genomic deletion is the primary route for tumor progression. To functionally identify putative tumor suppressors in GBM, we employed in vivo RNAi screening using patient-derived xenograft models. Here, we identified PIP4K2A, whose functional role and clinical ...
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Shin, Y. J., Sa, J. K., Lee, Y., Kim, D., Chang, N., Cho, H. J., Son, M., Oh, M. Y. T., Shin, K., Lee, J.-K., Park, J., Jo, Y. K., Kim, M., Paddison, P. J., Tergaonkar, V., Lee, J., Nam, D.-H. Tags: Solid Tumors, Neuroscience Articles Source Type: research

Adiponectin accounts for gender differences in hepatocellular carcinoma incidence
This study provides insight into adipose tissue to liver crosstalk and its gender relation during cancer development, having the potential to guide strategies for new cancer therapeutics. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Manieri, E., Herrera-Melle, L., Mora, A., Tomas-Loba, A., Leiva-Vega, L., Fernandez, D. I., Rodriguez, E., Moran, L., Hernandez-Cosido, L., Torres, J. L., Seoane, L. M., Cubero, F. J., Marcos, M., Sabio, G. Tags: Solid Tumors, Metabolism Articles Source Type: research

Tumor-associated factors are enriched in lymphatic exudate compared to plasma in metastatic melanoma patients
Liquid biopsies allow monitoring of cancer progression and detection of relapse, but reliable biomarkers in melanoma are lacking. Because secreted factors preferentially drain to lymphatic vessels before dilution in the blood, we hypothesized that lymph should be vastly enriched in cancer biomarkers. We characterized postoperative lymphatic exudate and plasma of metastatic melanoma patients after lymphadenectomy and found a dramatic enrichment in lymphatic exudate of tumor-derived factors and especially extracellular vesicles containing melanoma-associated proteins and miRNAs, with unique protein signatures reflecting earl...
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Broggi, M. A. S., Maillat, L., Clement, C. C., Bordry, N., Corthesy, P., Auger, A., Matter, M., Hamelin, R., Potin, L., Demurtas, D., Romano, E., Harari, A., Speiser, D. E., Santambrogio, L., Swartz, M. A. Tags: Solid Tumors, Tumor Immunology Articles Source Type: research

Use of extracellular vesicles from lymphatic drainage as surrogate markers of melanoma progression and BRAFV600E mutation
Liquid biopsies from cancer patients have the potential to improve diagnosis and prognosis. The assessment of surrogate markers of tumor progression in circulating extracellular vesicles could be a powerful non-invasive approach in this setting. We have characterized extracellular vesicles purified from the lymphatic drainage also known as exudative seroma (ES) of stage III melanoma patients obtained after lymphadenectomy. Proteomic analysis showed that seroma-derived exosomes are enriched in proteins resembling melanoma progression. In addition, we found that the BRAFV600E mutation can be detected in ES-derived extracellu...
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Garcia-Silva, S., Benito-Martin, A., Sanchez-Redondo, S., Hernandez-Barranco, A., Ximenez-Embun, P., Nogues, L., Mazariegos, M. S., Brinkmann, K., Amor Lopez, A., Meyer, L., Rodriguez, C., Garcia-Martin, C., Boskovic, J., Leton, R., Montero, C., Robledo, Tags: Solid Tumors, Human Disease Genetics Brief Definitive Reports Source Type: research

Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation
Studies of allelic variation underlying genetic blood disorders have provided important insights into human hematopoiesis. Most often, the identified pathogenic mutations result in loss-of-function or missense changes. However, assessing the pathogenicity of noncoding variants can be challenging. Here, we characterize two unrelated patients with a distinct presentation of dyserythropoietic anemia and other impairments in hematopoiesis associated with an intronic mutation in GATA1 that is 24 nucleotides upstream of the canonical splice acceptor site. Functional studies demonstrate that this single-nucleotide alteration lead...
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Abdulhay, N. J., Fiorini, C., Verboon, J. M., Ludwig, L. S., Ulirsch, J. C., Zieger, B., Lareau, C. A., Mi, X., Roy, A., Obeng, E. A., Erlacher, M., Gupta, N., Gabriel, S. B., Ebert, B. L., Niemeyer, C. M., Khoriaty, R. N., Ancliff, P., Gazda, H. T., Wlod Tags: Stem Cells & Regeneration, Hematopoiesis, Human Disease Genetics Brief Definitive Reports Source Type: research

Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity
CAR T cells represent a potentially curative strategy for B cell malignancies. However, the outcome and dynamics of CAR T cell interactions in distinct anatomical sites are poorly understood. Using intravital imaging, we tracked interactions established by anti-CD19 CAR T cells in B cell lymphoma–bearing mice. Circulating targets trapped CAR T cells in the lungs, reducing their access to lymphoid organs. In the bone marrow, tumor apoptosis was largely due to CAR T cells that engaged, killed, and detached from their targets within 25 min. Notably, not all CAR T cell contacts elicited calcium signaling or killing while...
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Cazaux, M., Grandjean, C. L., Lemaitre, F., Garcia, Z., Beck, R. J., Milo, I., Postat, J., Beltman, J. B., Cheadle, E. J., Bousso, P. Tags: Tumor Immunology Brief Definitive Reports Source Type: research

Aire-expressing ILC3-like cells in the lymph node display potent APC features
The autoimmune regulator (Aire) serves an essential function for T cell tolerance by promoting the "promiscuous" expression of tissue antigens in thymic epithelial cells. Aire is also detected in rare cells in peripheral lymphoid organs, but the identity of these cells is poorly understood. Here, we report that Aire protein–expressing cells in lymph nodes exhibit typical group 3 innate lymphoid cell (ILC3) characteristics such as lymphoid morphology, absence of "classical" hematopoietic lineage markers, and dependence on RORt. Aire+ cells are more frequent among lineage-negative RORt+ cells of peripheral lymph nodes ...
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Yamano, T., Dobes, J., Voboril, M., Steinert, M., Brabec, T., Zietara, N., Dobesova, M., Ohnmacht, C., Laan, M., Peterson, P., Benes, V., Sedlacek, R., Hanayama, R., Kolar, M., Klein, L., Filipp, D. Tags: Autoimmunity, Tolerance Brief Definitive Reports Source Type: research