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Science Immunology

Francisco J Quintana
Dissection of the heterogeneity of CNS myeloid cells reveals functionally distinct subsets that govern encephalitogenic T cells. See related Research Article by Jordão et al .
February 8, 2019: Science Immunology
Marta M Wegorzewska, Robert W P Glowacki, Samantha A Hsieh, David L Donermeyer, Christina A Hickey, Stephen C Horvath, Eric C Martens, Thaddeus S Stappenbeck, Paul M Allen
T cell responses to symbionts in the intestine drive tolerance or inflammation depending on the genetic background of the host. These symbionts in the gut sense the available nutrients and adapt their metabolic programs to use these nutrients efficiently. Here, we ask whether diet can alter the expression of a bacterial antigen to modulate adaptive immune responses. We generated a CD4+ T cell hybridoma, BθOM, specific for Bacteroides thetaiotaomicron ( B. theta ). Adoptively transferred transgenic T cells expressing the BθOM TCR proliferated in the colon, colon-draining lymph node, and spleen in B...
February 8, 2019: Science Immunology
Yang Cheng, Yuan O Zhu, Etienne Becht, Pauline Aw, Jinmiao Chen, Michael Poidinger, Paola Flórez de Sessions, Martin Lloyd Hibberd, Antonio Bertoletti, Seng Gee Lim, Evan W Newell
Associations between chronic antigen stimulation, T cell dysfunction, and the expression of various inhibitory receptors are well characterized in several mouse and human systems. During chronic hepatitis B virus (HBV) infection (CHB), T cell responses are blunted with low frequencies of virus-specific T cells observed, making these parameters difficult to study. Here, using mass cytometry and a highly multiplexed combinatorial peptide-major histocompatibility complex (pMHC) tetramer strategy that allows for the detection of rare antigen-specific T cells, we simultaneously probed 484 unique HLA-A*1101-restricted epitopes spanning the entire HBV genome on T cells from patients at various stages of CHB...
February 8, 2019: Science Immunology
Panos A Stathopoulos, Kevin C O'Connor
IgA-expressing antibody secreting cells that are formed in the gut travel to the brain to diminish inflammation during multiple sclerosis exacerbations.
February 1, 2019: Science Immunology
Jennifer S Chen, Stephanie C Eisenbarth
T follicular helper cells produce interleukin-10 during chronic viral infections to support the humoral response.
February 1, 2019: Science Immunology
Jacob M Luber, Aleksandar D Kostic
HLA haplotypes in conjunction with serum anticommensal antibody responses are predictive of type 1 diabetes progression. See related Research Article by Paun et al .
February 1, 2019: Science Immunology
Alexandra Paun, Christopher Yau, Shahab Meshkibaf, Michelle C Daigneault, Leili Marandi, Steven Mortin-Toth, Amit Bar-Or, Emma Allen-Vercoe, Philippe Poussier, Jayne S Danska
Microbiome sequence analyses have suggested that changes in gut bacterial composition are associated with autoimmune disease in humans and animal models. However, little is known of the mechanisms through which the gut microbiota influences autoimmune responses to distant tissues. Here, we evaluated systemic antibody responses against cultured human gut bacterial strains to determine whether observed patterns of anticommensal antibody (ACAb) responses are associated with type 1 diabetes (T1D) in two cohorts of pediatric study participants...
February 1, 2019: Science Immunology
Lelisa F Gemta, Peter J Siska, Marin E Nelson, Xia Gao, Xiaojing Liu, Jason W Locasale, Hideo Yagita, Craig L Slingluff, Kyle L Hoehn, Jeffrey C Rathmell, Timothy N J Bullock
In the context of solid tumors, there is a positive correlation between the accumulation of cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) and favorable clinical outcomes. However, CD8+ TILs often exhibit a state of functional exhaustion, limiting their activity, and the underlying molecular basis of this dysfunction is not fully understood. Here, we show that TILs found in human and murine CD8+ melanomas are metabolically compromised with deficits in both glycolytic and oxidative metabolism. Although several studies have shown that tumors can outcompete T cells for glucose, thus limiting T cell metabolic activity, we report that a down-regulation in the activity of ENOLASE 1, a critical enzyme in the glycolytic pathway, represses glycolytic activity in CD8+ TILs...
January 25, 2019: Science Immunology
Sarah Mundt, Dunja Mrdjen, Sebastian G Utz, Melanie Greter, Bettina Schreiner, Burkhard Becher
The central nervous system (CNS) is under close surveillance by immune cells, which mediate tissue homeostasis, protection, and repair. Conversely, in neuroinflammation, dysregulated leukocyte invasion into the CNS leads to immunopathology and neurological disability. To invade the brain parenchyma, autoimmune encephalitogenic T helper (TH ) cells must encounter their cognate antigens (Ags) presented via local Ag-presenting cells (APCs). The precise identity of the APC that samples, processes, and presents CNS-derived Ags to autoaggressive T cells is unknown...
January 25, 2019: Science Immunology
Claire Micossé, Leonhard von Meyenn, Oliver Steck, Enja Kipfer, Christian Adam, Cedric Simillion, S Morteza Seyed Jafari, Peter Olah, Nikhil Yawlkar, Dagmar Simon, Luca Borradori, Stefan Kuchen, Daniel Yerly, Bernhard Homey, Curdin Conrad, Berend Snijder, Marc Schmidt, Christoph Schlapbach
Although TH 1, TH 2, and TH 17 cells are well-defined TH cell lineages in humans, it remains debated whether IL-9-producing TH cells represent a bona fide "TH 9" lineage. Our understanding of the cellular characteristics and functions of IL-9-producing TH cells in humans is still nascent. Here, we report that human IL-9-producing TH cells express the chemokine receptors CCR4 and CCR8, produce high levels of IL-5 and IL-13, and express TH 2 lineage-associated transcription factors. In these cells, IL-9 production is activation dependent, transient, and accompanied by down-regulation of TH 2 cytokines, leading to an apparent "TH 9" phenotype...
January 18, 2019: Science Immunology
Stephanie E Ander, Michael S Diamond, Carolyn B Coyne
Pregnancy poses an immunological challenge because a genetically distinct (nonself) fetus must be supported within the pregnant female for the required gestational period. Placentation, or the establishment of the fetally derived placenta, is a common strategy used by eutherian mammals to protect the fetus and promote its growth. However, the substantial morphological differences of the placental architecture among species suggest that the process of placentation results from convergent evolution. Although there are considerable similarities in placental function across placental mammals, there are important differences that arise owing to species-specific immunological (and other biological) constraints...
January 11, 2019: Science Immunology
Mojgan Ahmadzadeh, Anna Pasetto, Li Jia, Drew C Deniger, Sanja Stevanović, Paul F Robbins, Steven A Rosenberg
CD4+ regulatory T (Treg ) cells have an essential function in maintaining self-tolerance; however, they may also play a detrimental role in antitumor immune responses. The presence of elevated frequencies of Treg cells in tumors correlates with disease progression and poor survival in patients with cancer. The antigen specificity of Treg cells that have expanded in the tumor microenvironment is poorly understood; answering this question may provide important insights for immunotherapeutic approaches. To address this, we used a novel combinatorial approach to characterizing the T cell receptor (TCR) profiles of intratumoral Treg cells from patients with metastatic melanoma, gastrointestinal, and ovarian cancers and elucidated their antigen specificities...
January 11, 2019: Science Immunology
Sarah E Henrickson
The immunometabolic pivot from reliance on fatty acid oxidation to glycolysis during T cell activation is, in part, reliant on the regulation of translation of key metabolic enzymes.
January 4, 2019: Science Immunology
Joshua M Moreau, Michael D Rosenblum
Commensal-specific T cells dually possess type-2 and type-17 effector potential, allowing plasticity in orchestrating tissue immunity.
January 4, 2019: Science Immunology
N Tsopoulidis, S Kaw, V Laketa, S Kutscheidt, C Baarlink, B Stolp, R Grosse, O T Fackler
T cell antigen receptor (TCR) signaling triggers selective cytokine expression to drive T cell proliferation and differentiation required for immune defense and surveillance. The nuclear signaling events responsible for specificity in cytokine gene expression upon T cell activation are largely unknown. Here, we uncover formation of a dynamic actin filament network in the nucleus that regulates cytokine expression for effector functions of CD4+ T lymphocytes. TCR engagement triggers the rapid and transient formation of a nuclear actin filament network via nuclear Arp2/3 complex, induced by elevated nuclear Ca2+ levels and regulated via N-Wasp and NIK...
January 4, 2019: Science Immunology
Stéphanie Boisson-Dupuis, Noe Ramirez-Alejo, Zhi Li, Etienne Patin, Geetha Rao, Gaspard Kerner, Che Kang Lim, Dimitry N Krementsov, Nicholas Hernandez, Cindy S Ma, Qian Zhang, Janet Markle, Ruben Martinez-Barricarte, Kathryn Payne, Robert Fisch, Caroline Deswarte, Joshua Halpern, Matthieu Bouaziz, Jeanette Mulwa, Durga Sivanesan, Tomi Lazarov, Rodrigo Naves, Patricia Garcia, Yuval Itan, Bertrand Boisson, Alix Checchi, Fabienne Jabot-Hanin, Aurélie Cobat, Andrea Guennoun, Carolyn C Jackson, Sevgi Pekcan, Zafer Caliskaner, Jaime Inostroza, Beatriz Tavares Costa-Carvalho, Jose Antonio Tavares de Albuquerque, Humberto Garcia-Ortiz, Lorena Orozco, Tayfun Ozcelik, Ahmed Abid, Ismail Abderahmani Rhorfi, Hicham Souhi, Hicham Naji Amrani, Adil Zegmout, Frédéric Geissmann, Stephen W Michnick, Ingrid Muller-Fleckenstein, Bernhard Fleckenstein, Anne Puel, Michael J Ciancanelli, Nico Marr, Hassan Abolhassani, María Elvira Balcells, Antonio Condino-Neto, Alexis Strickler, Katia Abarca, Cory Teuscher, Hans D Ochs, Ismail Reisli, Esra H Sayar, Jamila El-Baghdadi, Jacinta Bustamante, Lennart Hammarström, Stuart G Tangye, Sandra Pellegrini, Lluis Quintana-Murci, Laurent Abel, Jean-Laurent Casanova
Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common TYK2 P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls ( P = 8.37 × 10-8 ; odds ratio, 89...
December 21, 2018: Science Immunology
Rubén Martínez-Barricarte, Janet G Markle, Cindy S Ma, Elissa K Deenick, Noé Ramírez-Alejo, Federico Mele, Daniela Latorre, Seyed Alireza Mahdaviani, Caner Aytekin, Davood Mansouri, Vanessa L Bryant, Fabienne Jabot-Hanin, Caroline Deswarte, Alejandro Nieto-Patlán, Laura Surace, Gaspard Kerner, Yuval Itan, Sandra Jovic, Danielle T Avery, Natalie Wong, Geetha Rao, Etienne Patin, Satoshi Okada, Benedetta Bigio, Bertrand Boisson, Franck Rapaport, Yoann Seeleuthner, Monika Schmidt, Aydan Ikinciogullari, Figen Dogu, Gonul Tanir, Payam Tabarsi, Mohammed Reza Bloursaz, Julia K Joseph, Avneet Heer, Xiao-Fei Kong, Mélanie Migaud, Tomi Lazarov, Frédéric Geissmann, Bernhard Fleckenstein, Cecilia Lindestam Arlehamn, Alessandro Sette, Anne Puel, Jean-François Emile, Esther van de Vosse, Lluis Quintana-Murci, James P Di Santo, Laurent Abel, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Stuart G Tangye, Federica Sallusto, Jean-Laurent Casanova
Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rβ1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL-12-dependent IFN-γ immunity and IL-23-dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12Rβ2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis...
December 21, 2018: Science Immunology
Kelly A Remedios, Bahar Zirak, Priscila Munoz Sandoval, Margaret M Lowe, Devi Boda, Evan Henley, Shrishti Bhattrai, Tiffany C Scharschmidt, Wilson Liao, Haley B Naik, Michael D Rosenblum
Regulatory T cells (Tregs ) are closely related to TH 17 cells and use aspects of the TH 17-differentiation program for optimal immune regulation. In several chronic inflammatory human diseases, Tregs express IL-17A, suggesting that dysregulation of TH 17-associated pathways in Tregs may result in either loss of suppressive function and/or conversion into pathogenic cells. The pathways that regulate the TH 17 program in Tregs are poorly understood. We have identified two TNF receptor superfamily (TNFRSF) members, CD27 and OX40, that are preferentially expressed by skin-resident Tregs Both CD27 and OX40 signaling suppressed the expression of TH 17-associated genes from Tregs in a cell-intrinsic manner in vitro and in vivo...
December 21, 2018: Science Immunology
Patricia M Benveniste, Sobhan Roy, Munehide Nakatsugawa, Edward L Y Chen, Linh Nguyen, Douglas G Millar, Pamela S Ohashi, Naoto Hirano, Erin J Adams, Juan Carlos Zúñiga-Pflücker
Antigen recognition by T cells bearing αβ T cell receptors (TCRs) is restricted by major histocompatibility complex (MHC). However, how antigens are recognized by T cells bearing γδ TCRs remains unclear. Although γδ T cells can recognize nonclassical MHC, it is generally thought that recognition of antigens is not MHC restricted. Here, we took advantage of an in vitro system to generate antigen-specific human T cells and show that melanoma-associated antigens, MART-1 and gp100, can be recognized by γδ T cells in an MHC-restricted fashion...
December 14, 2018: Science Immunology
Regina Stark, Thomas H Wesselink, Felix M Behr, Natasja A M Kragten, Ramon Arens, Friedrich Koch-Nolte, Klaas P J M van Gisbergen, René A W van Lier
Tissue-resident memory T cells (TRM ) are noncirculating immune cells that contribute to the first line of local defense against reinfections. Their location at hotspots of pathogen encounter frequently exposes TRM to tissue damage. This history of danger-signal exposure is an important aspect of TRM -mediated immunity that has been overlooked so far. RNA profiling revealed that TRM from liver and small intestine express P2RX7, a damage/danger-associated molecular pattern (DAMP) receptor that is triggered by extracellular nucleotides (ATP, NAD+ )...
December 14, 2018: Science Immunology
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