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Mg2+ regulation of kinase signaling and immune function
Mg2+ is required at micromolar concentrations as a cofactor for ATP, enzymatic reactions, and other biological processes. We show that decreased extracellular Mg2+ reduced intracellular Mg2+ levels and impaired the Ca2+ flux, activation marker up-regulation, and proliferation after T cell receptor (TCR) stimulation. Reduced Mg2+ specifically impairs TCR signal transduction by IL-2–inducible T cell kinase (ITK) due to a requirement for a regulatory Mg2+ in the catalytic pocket of ITK. We also show that altered catalytic efficiency by millimolar changes in free basal Mg2+ is an unrecognized but conserved feature of oth...
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Kanellopoulou, C., George, A. B., Masutani, E., Cannons, J. L., Ravell, J. C., Yamamoto, T. N., Smelkinson, M. G., Jiang, P. D., Matsuda-Lennikov, M., Reilley, J., Handon, R., Lee, P.-H., Miller, J. R., Restifo, N. P., Zheng, L., Schwartzberg, P. L., Youn Tags: Infectious Disease and Host Defense Articles Source Type: research

The complex of MCMV proteins and MHC class I evades NK cell control and drives the evolution of virus-specific activating Ly49 receptors
CMVs efficiently target MHC I molecules to avoid recognition by cytotoxic T cells. However, the lack of MHC I on the cell surface renders the infected cell susceptible to NK cell killing upon missing self recognition. To counter this, mouse CMV (MCMV) rescues some MHC I molecules to engage inhibitory Ly49 receptors. Here we identify a new viral protein, MATp1, that is essential for MHC I surface rescue. Rescued altered-self MHC I molecules show increased affinity to inhibitory Ly49 receptors, resulting in inhibition of NK cells despite substantially reduced MHC I surface levels. This enables the virus to evade recognition ...
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Zeleznjak, J., Lisnic, V. J., Popovic, B., Lisnic, B., Babic, M., Halenius, A., LHernault, A., Rovis, T. L., Hengel, H., Erhard, F., Redwood, A. J., Vidal, S. M., Dölken, L., Krmpotic, A., Jonjic, S. Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense Articles Source Type: research

IL-27 promotes the expansion of self-renewing CD8+ T cells in persistent viral infection
Chronic infection and cancer are associated with suppressed T cell responses in the presence of cognate antigen. Recent work identified memory-like CXCR5+ TCF1+ CD8+ T cells that sustain T cell responses during persistent infection and proliferate upon anti-PD1 treatment. Approaches to expand these cells are sought. We show that blockade of interferon type 1 (IFN-I) receptor leads to CXCR5+ CD8+ T cell expansion in an IL-27– and STAT1-dependent manner. IFNAR1 blockade promoted accelerated cell division and retention of TCF1 in virus-specific CD8+ T cells. We found that CD8+ T cell–intrinsic IL-27 signaling safe...
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Huang, Z., Zak, J., Pratumchai, I., Shaabani, N., Vartabedian, V. F., Nguyen, N., Wu, T., Xiao, C., Teijaro, J. R. Tags: Stem Cells & Regeneration, Infectious Disease and Host Defense Articles Source Type: research

Inherited IL-18BP deficiency in human fulminant viral hepatitis
We report a child who died of FVH upon infection with hepatitis A virus (HAV) at age 11 yr and who was homozygous for a private 40-nucleotide deletion in IL18BP, which encodes the IL-18 binding protein (IL-18BP). This mutation is loss-of-function, unlike the variants found in a homozygous state in public databases. We show that human IL-18 and IL-18BP are both secreted mostly by hepatocytes and macrophages in the liver. Moreover, in the absence of IL-18BP, excessive NK cell activation by IL-18 results in uncontrolled killing of human hepatocytes in vitro. Inherited human IL-18BP deficiency thus underlies fulminant HAV hepa...
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Belkaya, S., Michailidis, E., Korol, C. B., Kabbani, M., Cobat, A., Bastard, P., Lee, Y. S., Hernandez, N., Drutman, S., de Jong, Y. P., Vivier, E., Bruneau, J., Beziat, V., Boisson, B., Lorenzo-Diaz, L., Boucherit, S., Sebagh, M., Jacquemin, E., Emile, J Tags: Immunodeficiency, Innate Immunity and Inflammation, Infectious Disease and Host Defense, Human Disease Genetics Articles Source Type: research

KLRG1 and NKp46 discriminate subpopulations of human CD117+CRTH2- ILCs biased toward ILC2 or ILC3
Recently, human ILCs that express CD117 and CD127 but lack CRTH2 and NKp44 have been shown to contain precursors of ILC1, ILC2, and ILC3. However, these ILCs have not been extensively characterized. We performed an unbiased hierarchical stochastic neighbor embedding (HSNE) analysis of the phenotype of peripheral blood CD117+ ILCs, which revealed the presence of three major subsets: the first expressed NKp46, the second expressed both NKp46 and CD56, and the third expressed KLRG1, but not NKp46 or CD56. Analysis of their cytokine production profiles and transcriptome revealed that NKp46+ ILCs predominantly develop into ILC3...
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Nagasawa, M., Heesters, B. A., Kradolfer, C. M. A., Krabbendam, L., Martinez-Gonzalez, I., de Bruijn, M. J. W., Golebski, K., Hendriks, R. W., Stadhouders, R., Spits, H., Bal, S. M. Tags: Innate Immunity and Inflammation Articles Source Type: research

E-protein-regulated expression of CXCR4 adheres preselection thymocytes to the thymic cortex
Preselection thymocytes are normally retained in the thymic cortex, but the mechanisms responsible remain incompletely understood. We now report that deletion of genes encoding the E-protein transcription factors E2A and HEB disorders chemokine receptor expression on developing thymocytes to allow escape of preselection TCR–CD8+ thymocytes into the periphery. We document that CXCR4 expression normally anchors preselection thymocytes to the thymic cortex via interaction with its ligand CXCL12 on cortical thymic epithelial cells, and that disruption of CXCR4–CXCL12 engagements release preselection thymocytes from...
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Kadakia, T., Tai, X., Kruhlak, M., Wisniewski, J., Hwang, I.-Y., Roy, S., Guinter, T. I., Alag, A., Kehrl, J. H., Zhuang, Y., Singer, A. Tags: Immunodeficiency Articles Source Type: research

CXCR4 regulates Plasmodium development in mouse and human hepatocytes
The liver stage of the etiological agent of malaria, Plasmodium, is obligatory for successful infection of its various mammalian hosts. Differentiation of the rod-shaped sporozoites of Plasmodium into spherical exoerythrocytic forms (EEFs) via bulbous expansion is essential for parasite development in the liver. However, little is known about the host factors regulating the morphological transformation of Plasmodium sporozoites in this organ. Here, we show that sporozoite differentiation into EEFs in the liver involves protein kinase C –mediated NF-B activation, which robustly induces the expression of C-X-C chemokin...
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Bando, H., Pradipta, A., Iwanaga, S., Okamoto, T., Okuzaki, D., Tanaka, S., Vega-Rodriguez, J., Lee, Y., Ma, J. S., Sakaguchi, N., Soga, A., Fukumoto, S., Sasai, M., Matsuura, Y., Yuda, M., Jacobs-Lorena, M., Yamamoto, M. Tags: Infectious Disease and Host Defense Brief Definitive Reports Source Type: research

JEM Editorial Board: Expanding on the basis of cancer
Immunotherapy has launched a new era for cancer treatment. Studies leading to the discovery of immune checkpoints and the effectiveness of their blockade have changed the way cancer patients are treated today. Over the last few decades, JEM has... (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Nathan, C. F., Nussenzweig, M. C., Pulvirenti, T. Tags: Editorial Source Type: research

Endothelial life discontinues without Erk
The mechanism of maintaining vascular endothelial identity and integrity is largely unknown. In this issue of JEM, Ricard et al. (https://doi.org/10.1084/jem.20182151) discover essential roles of ERK1/2 in maintaining endothelial homeostasis and its deletion-related serious defects in multiple tissues and organs. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Cao, Y. Tags: Cardiovascular Biology, Stem Cells & Regeneration Insights Source Type: research

No IL-18BP? Avoid HAV
Fulminant viral hepatitis occurs in a very small number of infected individuals. Until now, the basis for this phenotype has remained unknown. In this issue of JEM, Belkaya et al. (https://doi.org/10.1084/jem.20190669) identify a deletion in the IL18BP gene in a severely affected child that results in excessive natural killer cell activation and uncontrolled killing of hepatocytes. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Diamond, M. S. Tags: Insights Source Type: research

Plastic fantastic innate lymphoid cells
In this issue of JEM, Nagasawa et al. (https://doi.org/10.1084/jem.20190490) have undertaken a detailed study of the cell surface phenotype, transcriptional profile, and cytokine secretion of ILC progenitor populations in human peripheral blood and tissues and describe markers that highlight the heterogeneity of these chameleons. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Lanier, L. L. Tags: Insights Source Type: research

Immune homeostasis and regulation of the interferon pathway require myeloid-derived Regnase-3
The RNase Regnase-1 is a master RNA regulator in macrophages and T cells that degrades cellular and viral RNA upon NF-B signaling. The roles of its family members, however, remain largely unknown. Here, we analyzed Regnase-3–deficient mice, which develop hypertrophic lymph nodes. We used various mice with immune cell–specific deletions of Regnase-3 to demonstrate that Regnase-3 acts specifically within myeloid cells. Regnase-3 deficiency systemically increased IFN signaling, which increased the proportion of immature B and innate immune cells, and suppressed follicle and germinal center formation. Expression an...
Source: The Journal of Experimental Medicine - June 30, 2019 Category: Internal Medicine Authors: von Gamm, M., Schaub, A., Jones, A. N., Wolf, C., Behrens, G., Lichti, J., Essig, K., Macht, A., Pircher, J., Ehrlich, A., Davari, K., Chauhan, D., Busch, B., Wurst, W., Feederle, R., Feuchtinger, A., Tschöp, M. H., Friedel, C. C., Hauck, S. M., S Tags: Innate Immunity and Inflammation Articles Source Type: research

TCF-1 limits the formation of Tc17 cells via repression of the MAF-ROR{gamma}t axis
Interleukin (IL)-17–producing CD8+ T (Tc17) cells have emerged as key players in host-microbiota interactions, infection, and cancer. The factors that drive their development, in contrast to interferon (IFN)-–producing effector CD8+ T cells, are not clear. Here we demonstrate that the transcription factor TCF-1 (Tcf7) regulates CD8+ T cell fate decisions in double-positive (DP) thymocytes through the sequential suppression of MAF and RORt, in parallel with TCF-1–driven modulation of chromatin state. Ablation of TCF-1 resulted in enhanced Tc17 cell development and exposed a gene set signature to drive tiss...
Source: The Journal of Experimental Medicine - June 30, 2019 Category: Internal Medicine Authors: Mielke, L. A., Liao, Y., Clemens, E. B., Firth, M. A., Duckworth, B., Huang, Q., Almeida, F. F., Chopin, M., Koay, H.-F., Bell, C. A., Hediyeh-Zadeh, S., Park, S. L., Raghu, D., Choi, J., Putoczki, T. L., Hodgkin, P. D., Franks, A. E., Mackay, L. K., Godf Tags: Hematopoiesis Articles Source Type: research

The E3 ligase VHL promotes follicular helper T cell differentiation via glycolytic-epigenetic control
Follicular helper T (Tfh) cells are essential for germinal center formation and effective humoral immunity, which undergo different stages of development to become fully polarized. However, the detailed mechanisms of their regulation remain unsolved. Here we found that the E3 ubiquitin ligase VHL was required for Tfh cell development and function upon acute virus infection or antigen immunization. VHL acted through the hypoxia-inducible factor 1α (HIF-1α)–dependent glycolysis pathway to positively regulate early Tfh cell initiation. The enhanced glycolytic activity due to VHL deficiency was involved in th...
Source: The Journal of Experimental Medicine - June 30, 2019 Category: Internal Medicine Authors: Zhu, Y., Zhao, Y., Zou, L., Zhang, D., Aki, D., Liu, Y.-C. Tags: Metabolism Articles Source Type: research

CtIP is essential for early B cell proliferation and development in mice
B cell development requires efficient proliferation and successful assembly and modifications of the immunoglobulin gene products. CtIP is an essential gene implicated in end resection and DNA repair. Here, we show that CtIP is essential for early B cell development but dispensable in naive B cells. CtIP loss is well tolerated in G1-arrested B cells and during V(D)J recombination, but in proliferating B cells, CtIP loss leads to a progressive cell death characterized by ATM hyperactivation, G2/M arrest, genomic instability, and 53BP1 nuclear body formation, indicating that the essential role of CtIP during proliferation un...
Source: The Journal of Experimental Medicine - June 30, 2019 Category: Internal Medicine Authors: Liu, X., Wang, X. S., Lee, B. J., Wu-Baer, F. K., Lin, X., Shao, Z., Estes, V. M., Gautier, J., Baer, R., Zha, S. Tags: Genome Stability Articles Source Type: research