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Modulating inflammation for cancer therapy
A link between chronic inflammation and development of tumors is well established. Moreover, it has become evident that tumorigenesis is not a cell autonomous disease, and an inflammatory microenvironment is a prerequisite of basically all tumors, including those that emerge in the absence of overt inflammation. This knowledge has led to the development of anti-inflammatory concepts to treat and prevent cancer. In contrast, immunotherapies, in particular checkpoint inhibitors, representing the most significant progress in the therapy of several malignancies depend on the presence of a pro-inflammatory "hot" environment. He...
Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Ritter, B., Greten, F. R. Tags: Solid Tumors, Innate Immunity and Inflammation, Tumor Immunology Review Source Type: research

Correction: A novel human IL2RB mutation results in T and NK cell-driven immune dysregulation
Vol. 216, No. 6, June 3, 2019. 10.1084/jem.20182015. The authors regret that in the original version of Fig. S2 G, the plot for healthy pediatric (H. Ped) #1 CD4+ T cells was mistakenly replicated in... (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Fernandez, I. Z., Baxter, R. M., Garcia-Perez, J. E., Vendrame, E., Ranganath, T., Kong, D. S., Lundquist, K., Nguyen, T., Ogolla, S., Black, J., Galambos, C., Gumbart, J. C., Dawany, N., Kelsen, J. R., de Zoeten, E. F., Quinones, R., Eissa, H., Verneris, Tags: Corrections Source Type: research

BCL6 corepressor contributes to Th17 cell formation by inhibiting Th17 fate suppressors
CD4+ T helper 17 (Th17) cells protect vertebrate hosts from extracellular pathogens at mucosal surfaces. Th17 cells form from naive precursors when signals from the T cell antigen receptor (TCR) and certain cytokine receptors induce the expression of the RORt transcription factor, which activates a set of Th17-specific genes. Using T cell–specific loss-of-function experiments, we find that two components of the Polycomb repressive complex 1.1 (PRC1.1), BCL6 corepressor (BCOR) and KDM2B, which helps target the complex to unmethylated CpG DNA islands, are required for optimal Th17 cell formation in mice after Streptoco...
Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Kotov, J. A., Kotov, D. I., Linehan, J. L., Bardwell, V. J., Gearhart, M. D., Jenkins, M. K. Tags: Infectious Disease and Host Defense Articles Source Type: research

Phosphorylation-dependent Regnase-1 release from endoplasmic reticulum is critical in IL-17 response
Regnase-1 (also known as Zc3h12a or MCPIP-1) is an endoribonuclease involved in mRNA degradation of inflammation-associated genes. Regnase-1 is inactivated in response to external stimuli through post-translational modifications including phosphorylation, yet the precise role of phosphorylation remains unknown. Here, we demonstrate that interleukin (IL)-17 induces phosphorylation of Regnase-1 in an Act1-TBK1/IKKi–dependent manner, especially in nonhematopoietic cells. Phosphorylated Regnase-1 is released from the endoplasmic reticulum (ER) into the cytosol, thereby losing its mRNA degradation function, which leads to...
Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Tanaka, H., Arima, Y., Kamimura, D., Tanaka, Y., Takahashi, N., Uehata, T., Maeda, K., Satoh, T., Murakami, M., Akira, S. Tags: Innate Immunity and Inflammation Articles Source Type: research

Fyn kinase regulates misfolded {alpha}-synuclein uptake and NLRP3 inflammasome activation in microglia
Persistent microglia-mediated neuroinflammation is a major pathophysiological contributor to the progression of Parkinson’s disease (PD), but the cell-signaling mechanisms governing chronic neuroinflammation are not well understood. Here, we show that Fyn kinase, in conjunction with the class B scavenger receptor CD36, regulates the microglial uptake of aggregated human α-synuclein (αSyn), which is the major component of PD-associated Lewy bodies. αSyn can effectively mediate LPS-independent priming and activation of the microglial NLRP3 inflammasome. Fyn kinase regulates both of these processes; it...
Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Panicker, N., Sarkar, S., Harischandra, D. S., Neal, M., Kam, T.-I., Jin, H., Saminathan, H., Langley, M., Charli, A., Samidurai, M., Rokad, D., Ghaisas, S., Pletnikova, O., Dawson, V. L., Dawson, T. M., Anantharam, V., Kanthasamy, A. G., Kanthasamy, A. Tags: Neuroinflammation, Neuroscience Articles Source Type: research

Hes1 attenuates type I IFN responses via VEGF-C and WDFY1
Induction of type I interferons (IFNs) is critical for eliciting competent immune responses, especially antiviral immunity. However, uncontrolled IFN production contributes to pathogenesis of autoimmune and inflammatory diseases. We found that transcription factor Hes1 suppressed production of type I IFNs and expression of IFN-stimulated genes. Functionally, Hes1-deficient mice displayed a heightened IFN signature in vivo, mounted enhanced resistance against encephalomyocarditis virus infection, and showed signs of exacerbated experimental lupus nephritis. Mechanistically, Hes1 did not suppress IFNs via direct transcriptio...
Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Ning, F., Li, X., Yu, L., Zhang, B., Zhao, Y., Liu, Y., Zhao, B., Shang, Y., Hu, X. Tags: Autoimmunity, Innate Immunity and Inflammation Articles Source Type: research

Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET
Although abnormal nuclear structure is an important criterion for cancer diagnostics, remarkably little is known about its relationship to tumor development. Here we report that loss of lamin B1, a determinant of nuclear architecture, plays a key role in lung cancer. We found that lamin B1 levels were reduced in lung cancer patients. Lamin B1 silencing in lung epithelial cells promoted epithelial–mesenchymal transition, cell migration, tumor growth, and metastasis. Mechanistically, we show that lamin B1 recruits the polycomb repressive complex 2 (PRC2) to alter the H3K27me3 landscape and repress genes involved in cel...
Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Jia, Y., Vong, J. S.-L., Asafova, A., Garvalov, B. K., Caputo, L., Cordero, J., Singh, A., Boettger, T., Günther, S., Fink, L., Acker, T., Barreto, G., Seeger, W., Braun, T., Savai, R., Dobreva, G. Tags: Solid Tumors Articles Source Type: research

Oncogenic kinase inhibition limits Batf3-dependent dendritic cell development and antitumor immunity
Gastrointestinal stromal tumor (GIST) is driven by an activating mutation in the KIT proto-oncogene. Using a mouse model of GIST and human specimens, we show that intratumoral murine CD103+CD11b– dendritic cells (DCs) and human CD141+ DCs are associated with CD8+ T cell infiltration and differentiation. In mice, the antitumor effect of the Kit inhibitor imatinib is partially mediated by CD103+CD11b– DCs, and effector CD8+ T cells initially proliferate. However, in both mice and humans, chronic imatinib therapy decreases intratumoral DCs and effector CD8+ T cells. The mechanism in our mouse model depends on Kit ...
Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Medina, B. D., Liu, M., Vitiello, G. A., Seifert, A. M., Zeng, S., Bowler, T., Zhang, J. Q., Cavnar, M. J., Loo, J. K., Param, N. J., Maltbaek, J. H., Rossi, F., Balachandran, V., DeMatteo, R. P. Tags: Tumor Immunology Articles Source Type: research

Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer
Obesity is associated with increased incidence and severity of triple-negative breast cancer (TNBC); however, mechanisms underlying this relationship are incompletely understood. Here, we show that obesity reprograms mammary adipose tissue macrophages to a pro-inflammatory metabolically activated phenotype (MMe) that alters the niche to support tumor formation. Unlike pro-inflammatory M1 macrophages that antagonize tumorigenesis, MMe macrophages are pro-tumorigenic and represent the dominant macrophage phenotype in mammary adipose tissue of obese humans and mice. MMe macrophages release IL-6 in an NADPH oxidase 2 (NOX2)&nd...
Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Tiwari, P., Blank, A., Cui, C., Schoenfelt, K. Q., Zhou, G., Xu, Y., Khramtsova, G., Olopade, F., Shah, A. M., Khan, S. A., Rosner, M. R., Becker, L. Tags: Solid Tumors, Innate Immunity and Inflammation, Metabolism Articles Source Type: research

T cell anergy in perinatal mice is promoted by T reg cells and prevented by IL-33
Perinatal T cells broadly access nonlymphoid tissues, where they are exposed to sessile tissue antigens. To probe the outcome of such encounters, we examined the defective elimination of self-reactive clones in Aire-deficient mice. Nonlymphoid tissues were sequentially seeded by distinct waves of CD4+ T cells. Early arrivers were mostly Foxp3+ regulatory T (T reg) cells and metabolically active, highly proliferative conventional T cells (T conv cells). T conv cells had unusually high expression of PD-1 and the IL-33 receptor ST2. As T conv cells accumulated in the tissue, they gradually lost expression of ST2, ceased to pr...
Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Tuncel, J., Benoist, C., Mathis, D. Tags: Autoimmunity, Tolerance Articles Source Type: research

Human interleukin-2 receptor {beta} mutations associated with defects in immunity and peripheral tolerance
We report three homozygous mutations in the IL2RB gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rβ and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rβ expression and function. IL-2Rβ loss of function was recapitulated in a recombinant system in which IL2RB mutations caused redu...
Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Zhang, Z., Gothe, F., Pennamen, P., James, J. R., McDonald, D., Mata, C. P., Modis, Y., Alazami, A. M., Acres, M., Haller, W., Bowen, C., Döffinger, R., Sinclair, J., Brothers, S., Zhang, Y., Matthews, H. F., Naudion, S., Pelluard, F., Alajlan, H. Tags: Autoimmunity, Immunodeficiency, Human Disease Genetics Articles Source Type: research

Expression of factor V by resident macrophages boosts host defense in the peritoneal cavity
Macrophages resident in different organs express distinct genes, but understanding how this diversity fits into tissue-specific features is limited. Here, we show that selective expression of coagulation factor V (FV) by resident peritoneal macrophages in mice promotes bacterial clearance in the peritoneal cavity and serves to facilitate the well-known but poorly understood "macrophage disappearance reaction." Intravital imaging revealed that resident macrophages were nonadherent in peritoneal fluid during homeostasis. Bacterial entry into the peritoneum acutely induced macrophage adherence and associated bacterial phagocy...
Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Zhang, N., Czepielewski, R. S., Jarjour, N. N., Erlich, E. C., Esaulova, E., Saunders, B. T., Grover, S. P., Cleuren, A. C., Broze, G. J., Edelson, B. T., Mackman, N., Zinselmeyer, B. H., Randolph, G. J. Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense Brief Definitive Reports Source Type: research

Adaptive NK cells in people exposed to Plasmodium falciparum correlate with protection from malaria
How antibodies naturally acquired during Plasmodium falciparum infection provide clinical immunity to blood-stage malaria is unclear. We studied the function of natural killer (NK) cells in people living in a malaria-endemic region of Mali. Multi-parameter flow cytometry revealed a high proportion of adaptive NK cells, which are defined by the loss of transcription factor PLZF and Fc receptor -chain. Adaptive NK cells dominated antibody-dependent cellular cytotoxicity responses, and their frequency within total NK cells correlated with lower parasitemia and resistance to malaria. P. falciparum–infected RBCs induced N...
Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Hart, G. T., Tran, T. M., Theorell, J., Schlums, H., Arora, G., Rajagopalan, S., Sangala, A. D. J., Welsh, K. J., Traore, B., Pierce, S. K., Crompton, P. D., Bryceson, Y. T., Long, E. O. Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense Brief Definitive Reports Source Type: research

The Notch signaling pathway promotes basophil responses during helminth-induced type 2 inflammation
Type 2 inflammation drives the clearance of gastrointestinal helminth parasites, which infect over two billion people worldwide. Basophils are innate immune cells that support host-protective type 2 inflammation during murine infection with the helminth Trichuris muris. However, the mechanisms required for basophil function and gene expression regulation in this context remain unclear. We show that during T. muris infection, basophils localized to the intestine and up-regulated Notch receptor expression, rendering them sensitive to Notch signals that rapidly regulate gene expression programs. In vitro, Notch inhibition lim...
Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Webb, L. M., Oyesola, O. O., Früh, S. P., Kamynina, E., Still, K. M., Patel, R. K., Peng, S. A., Cubitt, R. L., Grimson, A., Grenier, J. K., Harris, T. H., Danko, C. G., Tait Wojno, E. D. Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense, Mucosal Immunology Brief Definitive Reports Source Type: research

A novel human IL2RB mutation results in T and NK cell-driven immune dysregulation
The pleiotropic actions of interleukin-2 (IL-2) are essential for regulation of immune responses and maintenance of immune tolerance. The IL-2 receptor (IL-2R) is composed of IL-2Rα, IL-2Rβ, and IL-2R subunits, with defects in IL-2Rα and IL-2R and their downstream signaling effectors resulting in known primary immunodeficiency disorders. Here, we report the first human defect in IL-2Rβ, occurring in two infant siblings with a homozygous IL2RB mutation in the WSXWS motif, manifesting as multisystem autoimmunity and susceptibility to CMV infection. The hypomorphic mutation results in diminished IL-2R&be...
Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Fernandez, I. Z., Baxter, R. M., Garcia-Perez, J. E., Vendrame, E., Ranganath, T., Kong, D. S., Lundquist, K., Nguyen, T., Ogolla, S., Black, J., Galambos, C., Gumbart, J. C., Dawany, N., Kelsen, J. R., de Zoeten, E. F., Quinones, R., Eissa, H., Verneris, Tags: Autoimmunity, Immunodeficiency, Human Disease Genetics Brief Definitive Reports Source Type: research