Immunology
Abstract
Type 1 diabetes (T1D) is precipitated by the autoimmune destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans. Chemokines have been identified as major conductors of islet infiltration by autoaggressive leukocytes, including antigen-presenting cells and islet autoantigen-specific T cells. We have previously generated a roadmap of gene expression in the islet microenvironment during T1D in a mouse model and found that most of the chemokine axes are chronically upregulated during T1D. The XCL1/XCR1 chemokine axis is of particular interest, since XCR1 is exclusively expressed on conventional dendritic cells type 1 (cDC1) that excel by their high capacity for T cell activation. Here we demonstrate cDC1 expressing XCR1 are present in and around the islets of patients with T1D and of islet-autoantibody positive individuals. Further, we show that XCL1 plays an important role in the attraction of highly potent dendritic cells expressing XCR1 to the islets in an inducible mouse model for T1D. XCL1-deficient mice display a diminished infiltration of XCR1+ cDC1 and subsequently a reduced magnitude and activity of islet autoantigen-specific T cells resulting in a profound decrease in T1D incidence. Interference with the XCL1/XCR1 chemokine axis might constitute a novel therapy for T1D.
Authors
Camilla Tondello, Christine Bender, Gregory J. Golden, Deborah Puppe, Elisa Blickberndt, Monika Bayer, Giulia K. Buchmann, Josef Pfeilschifter, Malte Bachmann, Edith Hintermann, Ralf P. Brandes, Michael R. Betts, Richard A. Kroczek, Urs Christen
Abstract
While immune checkpoint inhibition (CPI) has reshaped cancer treatment, the majority of cancer patients do not benefit from this approach, which can also cause immune-related adverse events. Induction of IFNγ responses is thought be necessary for anti-tumor immunity, but growing evidence also implicates IFNγ as a tumor-intrinsic mediator of CPI resistance. CPI-induced IFNγ mediates activation-induced cell death in T cells as an immune-intrinsic mechanism of resistance. In this study, we show that transient block of IFNγ signaling through administration of the JAK1 inhibitor ABT-317 enhances anti-tumor T cell responses with CPI in pre-clinical models. Importantly, sequential but not concomitant ABT-317 treatment led to significantly reduced toxicity and improved tumor efficacy. Sequential treatment reduced activation-induced T cell death and enhanced expansion of tumor-reactive T cell subsets with increased effector function in vivo and ex vivo. Only CPI in combination with ABT-317 also enhanced memory responses by protecting mice from tumor rechallenge. These results demonstrate that JAK inhibition within a discrete time window following CPI addresses an immune-intrinsic mechanism of therapeutic resistance.
Authors
Marcel Arias-Badia, PeiXi Chen, Yee May Lwin, Aahir Srinath, Aram Lyu, Zenghua Fan, Serena S. Kwek, Diamond N. Luong, Ali Setayesh, Mason Sakamoto, Matthew Clark, Averey Lea, Rachel M. Wolters, Andrew Goodearl, Fiona A. Harding, Jacob V. Gorman, Wendy Ritacco, Lawrence Fong
Abstract
Chlamydia trachomatis (CT) is the most common bacterial sexually transmitted infection globally. Understanding natural immunity to CT will inform vaccine design. This study aimed to profile immune cells and associated functional features in CT-infected women, and determine immune profiles associated with reduced risk of ascended endometrial CT infection and CT reinfection. PBMCs from CT-exposed women were profiled by mass cytometry and random forest models identified key features that distinguish outcomes. CT+ participants exhibited higher frequencies of CD4+ Th2, Th17, and Th17 DN CD4 T effector memory (TEM) cells than uninfected participants with decreased expression of T cell activation and differentiation markers. Minimal differences were detected between women with or without endometrial CT infection. Participants who remained follow-up negative (FU-) showed higher frequencies of CD4 T central memory (TCM) Th1, Th17, Th1/17, and Th17 DN but reduced CD4 TEM Th2 cells than FU+ participants. Expression of markers associated with central memory and Th17 lineage were increased on T cell subsets among FU- participants. These data indicate that peripheral T cells exhibit distinct features associated with resistance to CT reinfection. The highly plastic Th17 lineage appears to contribute to protection. Addressing these immune nuances could promote efficacy of CT vaccines.
Authors
Kacy S. Yount, Chi-Jane Chen, Avinash Kollipara, Chuwen Liu, Neha Vivek Mokashi, Xiaojing Zheng, C Bruce Bagwell, Taylor B. Poston, Harold C. Wiesenfeld, Sharon L. Hillier, Catherine M. O'Connell, Natalie Stanley, Toni Darville
Abstract
The role of mesenchymal cells during respiratory infection is not well defined, including whether, which, and how the different types of mesenchymal cells respond. We collected all mesenchymal cells from lung single-cell suspensions of mice that were naïve (after receiving only saline vehicle), pneumonic (after intratracheal instillation of pneumococcus 24 hours previously), or resolved from infection (after non-lethal pneumococcal infections 6 weeks previously) and performed single-cell RNA sequencing. Cells clustered into five well-separated groups based on their transcriptomes: matrix fibroblasts, myofibroblasts, pericytes, smooth muscle cells, and mesothelial cells. Fibroblasts were the most abundant and could be further segregated into Pdgfra+Npnt+Ces1d+Col13a1+ alveolar fibroblasts and Cd9+Pi16+Sca1+Col14a1+ adventitial fibroblasts. The cells from naïve and resolved groups overlapped in dimension reduction plots, suggesting the mesenchymal cells returned to baseline transcriptomes after resolution. During pneumonia, all mesenchymal cells responded with altered transcriptomes, revealing a core response that had been conserved across cell types as well as distinct mesenchymal cell type-specific responses. The different subsets of fibroblasts induced similar gene sets, but the alveolar fibroblasts responded more strongly than the adventitial fibroblasts. These data demonstrated diverse and specialized immune activities of lung mesenchymal cells during pneumonia.
Authors
Alicia M. Soucy, Jourdan E. Brune, Archana Jayaraman, Anukul T. Shenoy, Filiz T. Korkmaz, Neelou S. Etesami, Bradley E. Hiller, Ian M.C. Martin, Wesley N. Goltry, Catherine T. Ha, Nicholas A. Crossland, Joshua D. Campbell, Thomas G. Beach, Katrina E. Traber, Matthew R. Jones, Lee J. Quinton, Markus Bosmann, Charles W. Frevert, Joseph P. Mizgerd
Abstract
The functional plasticity of tumor-infiltrating B (TIL-B) cells spans from anti-tumor responses to non-canonical immune suppression. Yet, how tumor microenvironment (TME) influences TIL-B development is still underappreciated. Our current study integrated single cell transcriptomics and BCR (B cell receptor) sequencing to profile TIL-B phenotypes and clonalities in hepatocellular carcinoma (HCC). Using trajectory and gene regulatory network analysis, we were able to characterize plasma cells, memory and naïve B cells within the HCC TME and further revealed a downregulation of BCR-signaling genes in plasma cells and a subset of inflammatory TNF+ memory B cells. Within the TME, non-switch memory B cell subset acquires an age-associated B cell phenotype (TBET+, CD11c+) and expressed higher levels of PD-L1, CD25 and granzyme B. We further demonstrated that the presence of HCC tumor cells could confer suppressive functions on peripheral blood B cells which in turn, dampen T cell co-stimulation. To the best of our knowledge, these findings represent novel mechanisms of non-canonical immune suppression in HCC. While previous studies identified atypical memory B cells in chronic hepatitis and across several solid cancer types, we further highlighted their potential role as regulatory B cells (Bregs) within both the TME and peripheral blood of HCC patients.
Authors
Shi Yong Neo, Timothy Wai Ho Shuen, Shruti Khare, Joni Chong, Maichan Lau, Niranjan Shirgaonkar, Levene Chua, Junzhe Zhao, Keene Lee, Charmaine Tan, Rebecca Ba, Janice Lim, Joelle Chua, Hui Shi Cheong, Hui Min Chai, Chung Yip Chan, Alexander Yaw Fui Chung, Peng Chung Cheow, Prema Raj Jeyaraj, Jin Yao Teo, Ye Xin Koh, Aik Yong Chok, Pierce Kah Hoe Chow, Brian Goh, Wei Keat Wan, Wei Qiang Leow, Tracy Jie Zhen Loh, Po Yin Tang, Jayanthi Karunanithi, Nye Thane Ngo, Tony Kiat Hon Lim, Shengli Xu, Ramanuj Dasgupta, Han Chong Toh, Kong-Peng Lam
Abstract
Chronic lung allograft dysfunction (CLAD) substantially limits long-term survival following lung transplantation. To identify potential targets for CLAD prevention, T cells from explanted CLAD lungs and lung-draining lymph nodes, as well as diseased and nondiseased controls were isolated and single-cell RNA sequencing and TCR sequencing were performed. TCR sequencing revealed a clonally expanded population of CD8+ tissue-resident memory T cells (TRMs) with high cytotoxic potential, including upregulation of KLRK1, encoding the co-receptor NKG2D. These cytotoxic CD8+ TRMs accumulated around the CLAD airways and had a 100-fold increase in clonal overlap with lung-draining lymph nodes when compared with non-CLAD lungs. Using a murine model of orthotopic lung transplantation, we confirmed that cytotoxic CD8+ TRM accumulation was due to chronic rejection and not transplantation alone. Furthermore, blocking NKG2D in vivo attenuated the airway remodeling following transplantation and diminished airway accumulation of CD8+ T cells. Our findings support NKG2D as a potential therapeutic target for CLAD, affecting cytotoxic CD8+ TRM accumulation.
Authors
Kaveh Moghbeli, Madeline A. Lipp, Marta Bueno, Andrew Craig, Michelle Rojas, Minahal Abbas, Zachary I. Lakkis, Byron Chuan, John Sembrat, Kentaro Noda, Daniel J. Kass, Kong Chen, Li Fan, Tim Oury, Zihe Zhou, Xingan Wang, John F. McDyer, Oliver Eickelberg, Mark E. Snyder
Abstract
Necrobiosis is a histologic term used to describe abnormal deposits of “degenerating” collagen within the skin. It can be found as an incidental finding in various granulomatous conditions, but is a hallmark of necrobiosis lipoidica (NL) and necrobiotic xanthogranuloma (NXG). There is limited prior research on necrobiosis. Here, we employed single-cell analysis of lesional and nonlesional skin to study the pathophysiology of necrobiosis. Our findings demonstrate that necrobiotic lesional skin is characterized by SPP1hi macrophages expressing MARCO; NKG7-expressing effector CD8+ T cells coexpressing CCL5, IFNG, GZMs, and PRF1; CCL5hi fibroblasts coexpressing CXCL9, diverse collagens (e.g., COL4A4, COL11A1, COL8A1), and TIMP1; and IGHM-expressing plasma cells. Integrative analysis of signaling ligands and receptor expression identified strong cell-cell communication between NKG7+ T cells, CCL5hi fibroblasts, and SPP1-expressing macrophages. In contrast, these cell populations were not dominant features of systemic sclerosis, another collagen deposition disease. Furthermore, although SPP1-expressing macrophages were detectable in sarcoidosis, IFNG-expressing T cells were a more defining feature of sarcoidosis compared with NL and NXG. From these findings, we speculate that necrobiosis results from the deposition of diverse collagens and ECM proteins through a process driven by CCL5-expressing fibroblasts and SPP1-expressing macrophages.
Authors
Stephanie T. Le, Alina I. Marusina, Alexander A. Merleev, Amanda Kirane, Olga Kruglinskaya, Andrey Kunitsyn, Nikolay Yu Kuzminykh, Xianying Xing, Sophie Y. Li, William Liakos, J. Michelle Kahlenberg, Andrea Gompers, Lauren Downing, Sahiti Marella, Allison C. Billi, Paul W. Harms, Lam C. Tsoi, Marie-Charlotte Brüggen, Iannis E. Adamopoulos, Johann E. Gudjonsson, Emanual Maverakis
Abstract
Dengue is widespread in tropical and subtropical regions globally and imposes a considerable disease burden. Annually, dengue virus (DENV) causes up to 400 million infections, of which approximately 25% present with clinical manifestations ranging from mild to fatal. Despite its significance as a growing public health concern, developing effective DENV vaccines has been challenging. One reason is the lack of comprehensive understanding of the influence exerted by prior DENV infections and immune responses with cross-reactive properties. To investigate this, we collected samples from a pediatric cohort study in dengue-endemic Managua, Nicaragua. We characterized T cell responses in 71 healthy children who had previously experienced 1 or more natural DENV infections and who, within 1 year after sample collection, had a subsequent DENV infection that was either symptomatic or inapparent. Our study investigated the effect of preexisting DENV-specific T cell responses on clinical outcomes of subsequent DENV infection. We assessed DENV-specific T cell responses using an activation-induced marker assay. Children with only 1 prior DENV infection displayed heterogeneous DENV-specific CD4+ and CD8+ T cell frequencies. In contrast, children with 2 or more prior DENV infections showed significantly higher DENV-specific CD4+ and CD8+ T cell frequencies associated with inapparent rather than symptomatic outcomes in subsequent infection. These findings demonstrate the protective role of DENV-specific T cells against symptomatic DENV infection and advance efforts to identify protective immune correlates against dengue.
Authors
Rosa Isela Gálvez, Amparo Martínez-Pérez, E. Alexandar Escarrega, Tulika Singh, José Victor Zambrana, Ángel Balmaseda, Eva Harris, Daniela Weiskopf
Abstract
Access to the brain for treating neurological sequalae requires a craniotomy, which can be complicated by infection. Staphylococcus aureus accounts for half of craniotomy infections, increasing morbidity in a medically fragile patient population. T cells preferentially traffic to the brain during craniotomy infection; however, their functional importance is unknown. Using a mouse model of S. aureus craniotomy infection, CD4+ T cells were critical for bacterial containment, as treatment of WT animals with anti-CD4 exacerbated infection that was similar to phenotypes in Rag1–/– mice. Single-cell RNA-Seq (scRNA-Seq) revealed transcriptional heterogeneity in brain CD3+ infiltrates, with CD4+ cells most prominent that displayed Th1- and Th17-like characteristics, and adoptive transfer of either subset in Rag1–/– animals during early infection prevented S. aureus outgrowth. scRNA-Seq identified a robust IFN signature in several innate immune clusters, and examination of cell-to-cell interactions revealed extensive T cell crosstalk with monocytes/macrophages that was also observed in human craniotomy infection. A cooperative role for Th1 and Th17 responses was demonstrated by treatment of Ifng–/– mice with IL-17A neutralizing antibody that recapitulated phenotypes in Rag1–/– animals. Collectively, these findings implicate Th1- and Th17-mediated proinflammatory responses in shaping the innate immune landscape for S. aureus containment during craniotomy infection.
Authors
Gunjan Kak, Zachary Van Roy, Rachel W. Fallet, Lee E. Korshoj, Tammy Kielian
Abstract
Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring and loss of lung function. With limited treatment options, patients succumb to the disease within 2 to 5 years. The molecular pathogenesis of IPF regarding the immunologic changes that occur is poorly understood. We characterize a role for non-canonical aryl-hydrocarbon receptor signaling (ncAHR) in dendritic cells (DCs) that leads to production of IL-6 and increased IL-17+ cells, promoting fibrosis. TLR9 signaling in myofibroblasts is shown to regulate production of TDO2 which converts tryptophan into the endogenous AHR ligand kynurenine. Mice with augmented ncAHR signaling were created by crossing floxed AHR exon-2 deletion mice (AHRΔex2) with mice harboring a CD11c-Cre. Bleomycin (blm) was used to study fibrotic pathogenesis. Isolated CD11c+ cells and primary fibroblasts were treated ex-vivo with relevant TLR agonists and AHR modulating compounds to study how AHR signaling influenced inflammatory cytokine production. Human datasets were also interrogated. Inhibition of all AHR signaling rescued fibrosis, however, AHRΔex2 mice treated with blm developed more fibrosis and DCs from these mice were hyperinflammatory and profibrotic upon adoptive transfer. Treatment of fibrotic fibroblasts with TLR9 agonist increased expression of TDO2 and fibrotic fibroblasts activated IL-6 production in CD103+ DCs. Study of human samples corroborates the relevance of these findings in IPF patients. We also, for the first time, identify that AHR exon-2 floxed mice retain capacity for ncAHR signaling.
Authors
Hannah Carter, Rita Medina Costa, Taylor S. Adams, Talon M. Gilchrist, Claire E. Emch, Monica Bame, Justin M. Oldham, Steven K. Huang, Angela L. Linderholm, Imre Noth, Naftali Kaminski, Bethany B. Moore, Stephen J. Gurczynski
No posts were found with this tag.
