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Andreia C Lino, Van Duc Dang, Vicky Lampropoulou, Anna Welle, Jara Joedicke, Jelka Pohar, Quentin Simon, Jessie Thalmensi, Aurelia Baures, Vinciane Flühler, Imme Sakwa, Ulrik Stervbo, Stefanie Ries, Luc Jouneau, Pierre Boudinot, Takeshi Tsubata, Takahiro Adachi, Andreas Hutloff, Thomas Dörner, Ursula Zimber-Strobl, Alex F de Vos, Katja Dahlke, Gunnar Loh, Sarantis Korniotis, Christian Goosmann, Jean-Claude Weill, Claude-Agnès Reynaud, Stefan H E Kaufmann, Jörn Walter, Simon Fillatreau
B lymphocytes can suppress immunity through interleukin (IL)-10 production in infectious, autoimmune, and malignant diseases. Here, we have identified a natural plasma cell subset that distinctively expresses the inhibitory receptor LAG-3 and mediates this function in vivo. These plasma cells also express the inhibitory receptors CD200, PD-L1, and PD-L2. They develop from various B cell subsets in a B cell receptor (BCR)-dependent manner independently of microbiota in naive mice. After challenge they upregulate IL-10 expression via a Toll-like receptor-driven mechanism within hours and without proliferating...
July 2, 2018: Immunity
Mingchao Wang, Shanshan Zhang, Guoxing Zheng, Junjiu Huang, Zhou Songyang, Xueqiang Zhao, Xin Lin
Genetic mutations of CARD14 (encoding CARMA2) are observed in psoriasis patients. Here we showed that Card14E138A/+ and Card14ΔQ136/+ mice developed spontaneous psoriasis-like skin inflammation, which resulted from constitutively activated CARMA2 via self-aggregation leading to the enhanced activation of the IL-23-IL-17A cytokine axis. Card14-/- mice displayed attenuated skin inflammation in the imiquimod-induced psoriasis model due to impaired IL-17A signaling in keratinocytes. CARMA2, mainly expressed in keratinocytes, associates with the ACT1-TRAF6 signaling complex and mediates IL-17A-induced NF-κB and MAPK signaling pathway activation, which leads to expression of pro-inflammatory factors...
June 28, 2018: Immunity
Jinyang Li, Katelyn T Byrne, Fangxue Yan, Taiji Yamazoe, Zeyu Chen, Timour Baslan, Lee P Richman, Jeffrey H Lin, Yu H Sun, Andrew J Rech, David Balli, Ceire A Hay, Yogev Sela, Allyson J Merrell, Shannon M Liudahl, Naomi Gordon, Robert J Norgard, Salina Yuan, Sixiang Yu, Timothy Chao, Shuai Ye, T S Karin Eisinger-Mathason, Robert B Faryabi, John W Tobias, Scott W Lowe, Lisa M Coussens, E John Wherry, Robert H Vonderheide, Ben Z Stanger
The biological and functional heterogeneity between tumors-both across and within cancer types-poses a challenge for immunotherapy. To understand the factors underlying tumor immune heterogeneity and immunotherapy sensitivity, we established a library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma. These clones generated tumors that recapitulated T cell-inflamed and non-T-cell-inflamed tumor microenvironments upon implantation in immunocompetent mice, with distinct patterns of infiltration by immune cell subsets...
June 23, 2018: Immunity
Myunghoo Kim, Carolina Galan, Andrea A Hill, Wan-Jung Wu, Hannah Fehlner-Peach, Hyo Won Song, Deborah Schady, Matthew L Bettini, Kenneth W Simpson, Randy S Longman, Dan R Littman, Gretchen E Diehl
The intestinal barrier is vulnerable to damage by microbiota-induced inflammation that is normally restrained through mechanisms promoting homeostasis. Such disruptions contribute to autoimmune and inflammatory diseases including inflammatory bowel disease. We identified a regulatory loop whereby, in the presence of the normal microbiota, intestinal antigen-presenting cells (APCs) expressing the chemokine receptor CX3 CR1 reduced expansion of intestinal microbe-specific T helper 1 (Th1) cells and promoted generation of regulatory T cells responsive to food antigens and the microbiota itself...
June 21, 2018: Immunity
Zhizhang Wang, Weijie Yin, Lizhen Zhu, Jia Li, Yikun Yao, Feifei Chen, Mengmeng Sun, Jiayuan Zhang, Nan Shen, Yan Song, Xing Chang
Iron deposition is frequently observed in human autoinflammatory diseases, but its functional significance is largely unknown. Here we showed that iron promoted proinflammatory cytokine expression in T cells, including GM-CSF and IL-2, via regulating the stability of an RNA-binding protein PCBP1. Iron depletion or Pcbp1 deficiency in T cells inhibited GM-CSF production by attenuating Csf2 3' untranslated region (UTR) activity and messenger RNA stability. Pcbp1 deficiency or iron uptake blockade in autoreactive T cells abolished their capacity to induce experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis...
June 21, 2018: Immunity
Marko Šestan, Sonja Marinović, Inga Kavazović, Đurđica Cekinović, Stephan Wueest, Tamara Turk Wensveen, Ilija Brizić, Stipan Jonjić, Daniel Konrad, Felix M Wensveen, Bojan Polić
Pro-inflammatory cytokines of a T helper-1-signature are known to promote insulin resistance (IR) in obesity, but the physiological role of this mechanism is unclear. It is also unknown whether and how viral infection induces loss of glycemic control in subjects at risk for developing diabetes mellitus type 2 (DM2). We have found in mice and humans that viral infection caused short-term systemic IR. Virally-induced interferon-γ (IFN-γ) directly targeted skeletal muscle to downregulate the insulin receptor but did not cause loss of glycemic control because of a compensatory increase of insulin production...
June 20, 2018: Immunity
Sathish Babu Vasamsetti, Jonathan Florentin, Emilie Coppin, Lotte C A Stiekema, Kang H Zheng, Muhammad Umer Nisar, John Sembrat, David J Levinthal, Mauricio Rojas, Erik S G Stroes, Kang Kim, Partha Dutta
There is a growing body of research on the neural control of immunity and inflammation. However, it is not known whether the nervous system can regulate the production of inflammatory myeloid cells from hematopoietic progenitor cells in disease conditions. Myeloid cell numbers in diabetic patients were strongly correlated with plasma concentrations of norepinephrine, suggesting the role of sympathetic neuronal activation in myeloid cell production. The spleens of diabetic patients and mice contained higher numbers of tyrosine hydroxylase (TH)-expressing leukocytes that produced catecholamines...
June 18, 2018: Immunity
Yuki Morimoto, Kiyoshi Hirahara, Masahiro Kiuchi, Tomoko Wada, Tomomi Ichikawa, Toshio Kanno, Mikiko Okano, Kota Kokubo, Atsushi Onodera, Daiju Sakurai, Yoshitaka Okamoto, Toshinori Nakayama
Memory T cells provide long-lasting protective immunity, and distinct subpopulations of memory T cells drive chronic inflammatory diseases such as asthma. Asthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. The immunological mechanisms that induce airway fibrotic changes remain unknown. We found that interleukin-33 (IL-33) enhanced amphiregulin production by the IL-33 receptor, ST2hi memory T helper 2 (Th2) cells. Amphiregulin-epidermal growth factor receptor (EGFR)-mediated signaling directly reprogramed eosinophils to an inflammatory state with enhanced production of osteopontin, a key profibrotic immunomodulatory protein...
June 4, 2018: Immunity
Anke Di, Shiqin Xiong, Zhiming Ye, R K Subbarao Malireddi, Satoshi Kometani, Ming Zhong, Manish Mittal, Zhigang Hong, Thirumala-Devi Kanneganti, Jalees Rehman, Asrar B Malik
Potassium (K+ ) efflux across the plasma membrane is thought to be an essential mechanism for ATP-induced NLRP3 inflammasome activation, yet the identity of the efflux channel has remained elusive. Here we identified the two-pore domain K+ channel (K2P ) TWIK2 as the K+ efflux channel triggering NLRP3 inflammasome activation. Deletion of Kcnk6 (encoding TWIK2) prevented NLRP3 activation in macrophages and suppressed sepsis-induced lung inflammation. Adoptive transfer of Kcnk6-/- macrophages into mouse airways after macrophage depletion also prevented inflammatory lung injury...
June 4, 2018: Immunity
Timotheus Y F Halim, Batika M J Rana, Jennifer A Walker, Bernhard Kerscher, Martin D Knolle, Helen E Jolin, Eva M Serrao, Liora Haim-Vilmovsky, Sarah A Teichmann, Hans-Reimer Rodewald, Marina Botto, Timothy J Vyse, Padraic G Fallon, Zhi Li, David R Withers, Andrew N J McKenzie
The local regulation of type 2 immunity relies on dialog between the epithelium and the innate and adaptive immune cells. Here we found that alarmin-induced expression of the co-stimulatory molecule OX40L on group 2 innate lymphoid cells (ILC2s) provided tissue-restricted T cell co-stimulation that was indispensable for Th2 and regulatory T (Treg) cell responses in the lung and adipose tissue. Interleukin (IL)-33 administration resulted in organ-specific surface expression of OX40L on ILC2s and the concomitant expansion of Th2 and Treg cells, which was abolished upon deletion of OX40L on ILC2s (Il7raCre/+ Tnfsf4fl/fl mice)...
May 31, 2018: Immunity
Jialie Luo, Aihua Qian, Landon K Oetjen, Weihua Yu, Pu Yang, Jing Feng, Zili Xie, Shenbin Liu, Shijin Yin, Dari Dryn, Jizhong Cheng, Terrence E Riehl, Alexander V Zholos, William F Stenson, Brian S Kim, Hongzhen Hu
Intestinal macrophages are critical for gastrointestinal (GI) homeostasis, but our understanding of their role in regulating intestinal motility is incomplete. Here, we report that CX3C chemokine receptor 1-expressing muscularis macrophages (MMs) were required to maintain normal GI motility. MMs expressed the transient receptor potential vanilloid 4 (TRPV4) channel, which senses thermal, mechanical, and chemical cues. Selective pharmacologic inhibition of TRPV4 or conditional deletion of TRPV4 from macrophages decreased intestinal motility and was sufficient to reverse the GI hypermotility that is associated with chemotherapy treatment...
May 30, 2018: Immunity
Roel G J Klein Wolterink, Roksana M Pirzgalska, Henrique Veiga-Fernandes
Pulmonary neuroimmune networks have emerged as important regulators of lung homeostasis. In a recent issue of Science, Sui et al. show that strategically positioned pulmonary neuroendocrine cells amplify allergic airway responses via group 2 innate lymphoid cells.
July 17, 2018: Immunity
Kaitlin Kiernan, Nancie J MacIver
In this issue of Immunity, Šestan et al. (2018) show that viral-induced inflammation leads to insulin resistance in skeletal muscle, followed by compensatory hyperinsulinemia, which promotes the anti-viral effector response of CD8+ T cells. Interestingly, this leads to persistent glucose intolerance and the progression of type 2 diabetes in pre-diabetic animals.
July 17, 2018: Immunity
Pratyusha Mandal, Yanjun Feng, John D Lyons, Scott B Berger, Shunsuke Otani, Alexandra DeLaney, Gregory K Tharp, Kristal Maner-Smith, Eileen M Burd, Michelle Schaeffer, Sandra Hoffman, Carol Capriotti, Linda Roback, Cedrick B Young, Zhe Liang, Eric A Ortlund, Nelson C DiPaolo, Steven Bosinger, John Bertin, Peter J Gough, Igor E Brodsky, Craig M Coopersmith, Dmitry M Shayakhmetov, Edward S Mocarski
The execution of shock following high dose E. coli lipopolysaccharide (LPS) or bacterial sepsis in mice required pro-apoptotic caspase-8 in addition to pro-pyroptotic caspase-11 and gasdermin D. Hematopoietic cells produced MyD88- and TRIF-dependent inflammatory cytokines sufficient to initiate shock without any contribution from caspase-8 or caspase-11. Both proteases had to be present to support tumor necrosis factor- and interferon-β-dependent tissue injury first observed in the small intestine and later in spleen and thymus...
July 17, 2018: Immunity
Hélène Descamps, Christoph A Thaiss
The intestinal immune system performs a tightrope walk between anti-pathogen immunity and tolerance to innocuous luminal antigens. In this issue of Immunity, Kim et al. (2018) demonstrate that the microbiota is driving tolerance to food antigens and dampening inflammatory responses through CX3 CR1+ mononuclear phagocytes.
July 17, 2018: Immunity
Marija S Nadjsombati, John W McGinty, Miranda R Lyons-Cohen, James B Jaffe, Lucian DiPeso, Christoph Schneider, Corey N Miller, Joshua L Pollack, G A Nagana Gowda, Mary F Fontana, David J Erle, Mark S Anderson, Richard M Locksley, Daniel Raftery, Jakob von Moltke
In the small intestine, type 2 responses are regulated by a signaling circuit that involves tuft cells and group 2 innate lymphoid cells (ILC2s). Here, we identified the microbial metabolite succinate as an activating ligand for small intestinal (SI) tuft cells. Sequencing analyses of tuft cells isolated from the small intestine, gall bladder, colon, thymus, and trachea revealed that expression of tuft cell chemosensory receptors is tissue specific. SI tuft cells expressed the succinate receptor (SUCNR1), and providing succinate in drinking water was sufficient to induce a multifaceted type 2 immune response via the tuft-ILC2 circuit...
July 17, 2018: Immunity
David Wallach, Tae-Bong Kang
Cell-culture studies are our main source of knowledge of the various forms of programmed cell death. Yet genetic perturbations of death-protein function in animal models are almost the only source of our knowledge of the physiological roles of these programs. Shortcomings in the state of knowledge acquired by these two experimental approaches are exemplified in this Perspective by reference to research on the contribution of apoptosis to lymphocyte development, a subject on which there is already much knowledge, and on the role of necroptosis in inflammation, about which information is just beginning to emerge...
July 17, 2018: Immunity
P'ng Loke, Ken Cadwell
How type 2 immune responses are initiated is obscure. Nadjsombati et al. (2018), along with two other studies (Lei et al., 2018; Schneider et al., 2018), show that tuft cells can initiate type 2 responses by recognizing the metabolite succinate produced by intestinal parasites.
July 17, 2018: Immunity
Marit J van Gils, Rogier W Sanders
The HIV-1 fusion peptide is a target for broadly neutralizing antibodies. In a recent issue of Nature Medicine, Xu et al. (2018) provide proof-of-concept that vaccination with fusion peptide followed by vaccination with an envelope glycoprotein trimer can induce antibodies in animal models that neutralize diverse HIV-1 viruses.
July 17, 2018: Immunity
Brendan Horton, Stefani Spranger
Pancreatic adenocarcinoma (PDAC) is mostly refractory to immunotherapies. In this issue of Immunity, Li et al. (2018) generate a library of clonal PDAC tumors to examine the tumor-intrinsic features shaping the anti-tumor immune response and find that tumor cell-derived CXCL1 directly blunts T cell infiltration and reduces responsiveness to immunotherapy.
July 17, 2018: Immunity
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