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Cell circuits between B cell progenitors and IL-7+ mesenchymal progenitor cells control B cell development
B cell progenitors require paracrine signals such as interleukin-7 (IL-7) provided by bone marrow stromal cells for proliferation and survival. Yet, how B cells regulate access to these signals in vivo remains unclear. Here we show that proB and IL-7+ cells form a cell circuit wired by IL-7R signaling, which controls CXCR4 and focal adhesion kinase (FAK) expression and restricts proB cell movement due to increased adhesion to IL-7+CXCL12Hi cells. PreBCR signaling breaks this circuit by switching the preB cell behavior into a fast-moving and lower-adhesion state via increased CXCR4 and reduced FAK/α4β1 expression...
Source: The Journal of Experimental Medicine - October 1, 2018 Category: Internal Medicine Authors: Fistonich, C., Zehentmeier, S., Bednarski, J. J., Miao, R., Schjerven, H., Sleckman, B. P., Pereira, J. P. Tags: Leukemia & Lymphoma, Hematopoiesis Articles Source Type: research

Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency
We report a 5-yr-old child with severe pulmonary influenza at 2 yr. She is homozygous for a loss-of-function IRF9 allele. Her cells activate gamma-activated factor (GAF) STAT1 homodimers but not IFN-stimulated gene factor 3 (ISGF3) trimers (STAT1/STAT2/IRF9) in response to IFN-α2b. The transcriptome induced by IFN-α2b in the patient’s cells is much narrower than that of control cells; however, induction of a subset of IFN-stimulated gene transcripts remains detectable. In vitro, the patient’s cells do not control three respiratory viruses, influenza A virus (IAV), parainfluenza virus (PIV), and resp...
Source: The Journal of Experimental Medicine - October 1, 2018 Category: Internal Medicine Authors: Hernandez, N., Melki, I., Jing, H., Habib, T., Huang, S. S. Y., Danielson, J., Kula, T., Drutman, S., Belkaya, S., Rattina, V., Lorenzo-Diaz, L., Boulai, A., Rose, Y., Kitabayashi, N., Rodero, M. P., Dumaine, C., Blanche, S., Lebras, M.-N., Leung, M. C., Tags: Immunodeficiency, Innate Immunity and Inflammation, Human Disease Genetics Articles Source Type: research

Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors
Cognitive impairment occurs in 40–90% of patients with systemic lupus erythematosus (SLE), which is characterized by autoantibodies to nuclear antigens, especially DNA. We discovered that a subset of anti-DNA antibodies, termed DNRAbs, cross reacts with the N-methyl-d-aspartate receptor (NMDAR) and enhances NMDAR signaling. In patients, DNRAb presence associates with spatial memory impairment. In a mouse model, DNRAb-mediated brain pathology proceeds through an acute phase of excitotoxic neuron loss, followed by persistent alteration in neuronal integrity and spatial memory impairment. The latter pathology becomes ev...
Source: The Journal of Experimental Medicine - October 1, 2018 Category: Internal Medicine Authors: Nestor, J., Arinuma, Y., Huerta, T. S., Kowal, C., Nasiri, E., Kello, N., Fujieda, Y., Bialas, A., Hammond, T., Sriram, U., Stevens, B., Huerta, P. T., Volpe, B. T., Diamond, B. Tags: Autoimmunity Articles Source Type: research

Macrophages of distinct origins contribute to tumor development in the lung
Tissue-resident macrophages can self-maintain without contribution of adult hematopoiesis. Herein we show that tissue-resident interstitial macrophages (Res-TAMs) in mouse lungs contribute to the pool of tumor-associated macrophages (TAMs) together with CCR2-dependent recruited macrophages (MoD-TAMs). Res-TAMs largely correlated with tumor cell growth in vivo, while MoD-TAMs accumulation was associated with enhanced tumor spreading. Both cell subsets were depleted after chemotherapy, but MoD-TAMs rapidly recovered and performed phagocytosis-mediated tumor clearance. Interestingly, anti-VEGF treatment combined with chemothe...
Source: The Journal of Experimental Medicine - October 1, 2018 Category: Internal Medicine Authors: Loyher, P.-L., Hamon, P., Laviron, M., Meghraoui-Kheddar, A., Goncalves, E., Deng, Z., Torstensson, S., Bercovici, N., Baudesson de Chanville, C., Combadiere, B., Geissmann, F., Savina, A., Combadiere, C., Boissonnas, A. Tags: Solid Tumors, Innate Immunity and Inflammation, Tumor Immunology Articles Source Type: research

High-dimensional single cell analysis identifies stem-like cytotoxic CD8+ T cells infiltrating human tumors
CD8+ T cells infiltrating tumors are largely dysfunctional, but whether a subset maintains superior functionality remains ill defined. By high-dimensional single cell analysis of millions of CD8+ T cells from 53 individuals with lung cancer, we defined those subsets that are enriched in tumors compared with cancer-free tissues and blood. Besides exhausted and activated cells, we identified CXCR5+ TIM-3– CD8+ T cells with a partial exhausted phenotype, while retaining gene networks responsible for stem-like plasticity and cytotoxicity, as revealed by single cell sequencing of the whole transcriptome. Ex vivo, CXCR5+ T...
Source: The Journal of Experimental Medicine - October 1, 2018 Category: Internal Medicine Authors: Brummelman, J., Mazza, E. M. C., Alvisi, G., Colombo, F. S., Grilli, A., Mikulak, J., Mavilio, D., Alloisio, M., Ferrari, F., Lopci, E., Novellis, P., Veronesi, G., Lugli, E. Tags: Solid Tumors, Tumor Immunology Articles Source Type: research

Sox12 promotes T reg differentiation in the periphery during colitis
Peripherally induced regulatory T (pT reg) cells play indispensable roles in regulating gut inflammation; however, the mechanism underling the differentiation of pT reg cells under inflammatory conditions remains largely unknown. Here, we show that the expression of Sox12, a member of SoxC family, is significantly induced in T reg cells in colitic mice. We also show that TCR–NFAT signaling induces Sox12 expression in CD4+ T cells. Although Sox12 is not required for the development of thymus-derived T reg (tT reg) cells, Sox12 is involved in the development of pT reg cells under inflammatory conditions in an adoptive ...
Source: The Journal of Experimental Medicine - October 1, 2018 Category: Internal Medicine Authors: Tanaka, S., Suto, A., Iwamoto, T., Kageyama, T., Tamachi, T., Takatori, H., Suzuki, K., Hirose, K., Ohara, O., Lefebvre, V., Nakajima, H. Tags: Brief Definitive Reports Source Type: research

Endothelial cell fitness dictates the source of regenerating liver vasculature
Neoangiogenesis plays a key role in diverse pathophysiological conditions, including liver regeneration. Yet, the source of new endothelial cells (ECs) remains elusive. By analyzing the regeneration of the liver vasculature in irradiation-based myeloablative and nonmyeloablative bone marrow transplantation mouse models, we discovered that neoangiogenesis in livers with intact endothelium was solely mediated by proliferation of resident ECs. However, following irradiation-induced EC damage, bone marrow–derived mononuclear cells were recruited and incorporated into the vasculature. Further experiments with direct bone ...
Source: The Journal of Experimental Medicine - October 1, 2018 Category: Internal Medicine Authors: Singhal, M., Liu, X., Inverso, D., Jiang, K., Dai, J., He, H., Bartels, S., Li, W., Abdul Pari, A. A., Gengenbacher, N., Besemfelder, E., Hui, L., Augustin, H. G., Hu, J. Tags: Cardiovascular Biology, Stem Cells & Regeneration Brief Definitive Reports Source Type: research

Activated PIK3CD drives innate B cell expansion yet limits B cell-intrinsic immune responses
Activated PI3K-delta syndrome (APDS) is an immunodeficiency caused by gain-of-function mutations in PIK3CD. This disease exhibits complex immune phenotypes including increased IgM, recurrent infection, and impaired vaccine responses. To better understand the impact of B cells in this disease, we generated an inducible model of the common APDS mutation (hPIK3CD-E1021K; referred to as aPIK3CD) and intercrossed these mice with B cell–specific Cre models. Mb1-aPIK3CD mice exhibited bone marrow B lymphopenia and, conversely, expansion of the peripheral innate B1a and MZ B cell compartments. aPIK3CD B cells manifest increa...
Source: The Journal of Experimental Medicine - October 1, 2018 Category: Internal Medicine Authors: Wray-Dutra, M. N., Al Qureshah, F., Metzler, G., Oukka, M., James, R. G., Rawlings, D. J. Tags: Immunodeficiency Brief Definitive Reports Source Type: research

PreB cells are moving on
In this issue of JEM, Fistonich et al. (https://doi.org/10.1084/jem.20180778) address how the bone marrow microenvironment supports diverse lineages through multiple developmental stages. Differential motility between pro- and preB cells results in differential IL-7 exposure, and, intriguingly, stromal cells respond to abnormal B cells by reducing Il7. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - October 1, 2018 Category: Internal Medicine Authors: Dixit, D., Schwab, S. R. Tags: Leukemia & Lymphoma, Hematopoiesis Insights Source Type: research

Pumping blood with self-reliance and cooperation
In this issue of JEM, Singhal et al. (https://doi.org/10.1084/jem.20180008) explore the cellular mechanisms involved in endothelial cell regeneration in the liver. Using a combination of myeloablative and nonmyeloablative approaches, the authors found that repair of the endothelium is mediated by endothelial cells themselves, but when injured, endothelial cells enlist myeloid counterparts that aid in vascular repair. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - October 1, 2018 Category: Internal Medicine Authors: Iruela-Arispe, M. L. Tags: Cardiovascular Biology Insights Source Type: research

Metabolic control of regulatory T cell stability and function by TRAF3IP3 at the lysosome
Metabolic programs are crucial for regulatory T (T reg) cell stability and function, but the underlying mechanisms that regulate T reg cell metabolism are elusive. Here, we report that lysosomal TRAF3IP3 acts as a pivotal regulator in the maintenance of T reg cell metabolic fitness. T reg–specific deletion of Traf3ip3 impairs T reg cell function, causing the development of inflammatory disorders and stronger antitumor T cell responses in mice. Excessive mechanistic target of rapamycin complex 1 (mTORC1)–mediated hyper-glycolytic metabolism is responsible for the instability of TRAF3IP3-deficient T reg cells. Me...
Source: The Journal of Experimental Medicine - September 3, 2018 Category: Internal Medicine Authors: Yu, X., Teng, X.-L., Wang, F., Zheng, Y., Qu, G., Zhou, Y., Hu, Z., Wu, Z., Chang, Y., Chen, L., Li, H.-B., Su, B., Lu, L., Liu, Z., Sun, S.-C., Zou, Q. Tags: Tumor Immunology, Tolerance Articles Source Type: research

Activated CARD11 accelerates germinal center kinetics, promoting mTORC1 and terminal differentiation
Activating mutations in the adapter protein CARD11 associated with diffuse large B cell lymphomas (DLBCLs) are predicted to arise during germinal center (GC) responses, leading to inappropriate activation of NF-B signaling. Here, we modeled the B cell–intrinsic impact of the L251P activating mutation in CARD11 (aCARD11) on the GC response. Global B cell aCARD11 expression led to a modest increase in splenic B cells and a severe reduction in B1 B cell numbers, respectively. Following T cell–dependent immunization, aCARD11 cells exhibited increased rates of GC formation, resolution, and differentiation. Restricti...
Source: The Journal of Experimental Medicine - September 3, 2018 Category: Internal Medicine Authors: Wray-Dutra, M. N., Chawla, R., Thomas, K. R., Seymour, B. J., Arkatkar, T., Sommer, K. M., Khim, S., Trapnell, C., James, R. G., Rawlings, D. J. Tags: Tumor Immunology Articles Source Type: research

B cell adaptor for PI3-kinase (BCAP) modulates CD8+ effector and memory T cell differentiation
CD8+ T cells respond to signals via the T cell receptor (TCR), costimulatory molecules, and immunoregulatory cytokines by developing into diverse populations of effector and memory cells. The relative strength of phosphoinositide 3-kinase (PI3K) signaling early in the T cell response can dramatically influence downstream effector and memory T cell differentiation. We show that initial PI3K signaling during T cell activation results in up-regulation of the signaling scaffold B cell adaptor for PI3K (BCAP), which further potentiates PI3K signaling and promotes the accumulation of CD8+ T cells with a terminally differentiated...
Source: The Journal of Experimental Medicine - September 3, 2018 Category: Internal Medicine Authors: Singh, M. D., Ni, M., Sullivan, J. M., Hamerman, J. A., Campbell, D. J. Tags: Infectious Disease and Host Defense Articles Source Type: research

BCAP links IL-1R to the PI3K-mTOR pathway and regulates pathogenic Th17 cell differentiation
This study establishes BCAP as a critical link between IL-1R and the metabolic status of activated T cells that ultimately regulates the differentiation of inflammatory Th17 cells. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - September 3, 2018 Category: Internal Medicine Authors: Deason, K., Troutman, T. D., Jain, A., Challa, D. K., Mandraju, R., Brewer, T., Ward, E. S., Pasare, C. Tags: Autoimmunity, Metabolism Articles Source Type: research

LPS inactivation by a host lipase allows lung epithelial cell sensitization for allergic asthma
We report here that acyloxyacyl hydrolase (AOAH), a host lipase that degrades and inactivates LPS, renders mice more susceptible to house dust mite (HDM)–induced allergic asthma. Lung epithelial cells from Aoah–/– mice are refractory to HDM stimulation, decreasing dendritic cell activation and Th2 responses. Antibiotic treatment that diminished commensal LPS-producing bacteria normalized Aoah–/– responses to HDM, while giving LPS intrarectally ameliorated asthma. Aoah–/– mouse feces, plasma, and lungs contained more bioactive LPS than did those of Aoah+/+ mice. By inactivating comm...
Source: The Journal of Experimental Medicine - September 3, 2018 Category: Internal Medicine Authors: Qian, G., Jiang, W., Zou, B., Feng, J., Cheng, X., Gu, J., Chu, T., Niu, C., He, R., Chu, Y., Lu, M. Tags: Mucosal Immunology Articles Source Type: research