Immunology
Abstract
Thy-1 (CD90) is a well-known marker of fibroblasts implicated in organ fibrosis, but its contribution to skin fibrosis remains unknown. We examined Thy-1 expression in scleroderma skin and its potential role as a biomarker and pathogenic factor in animal models of skin fibrosis. Skin from patients with systemic sclerosis demonstrates markedly elevated Thy-1 expression compared to controls, co-localizes with fibroblast activator protein (FAP) in the deep dermis, and is correlated with the severity of skin involvement (MRSS). Serial imaging of skin from Thy-1 YFP reporter mice by IVIS showed an increase in Thy-1 expression which correlated with onset and progression of fibrosis. In contrast to lung fibrosis, Thy-1 KO mice had attenuated skin fibrosis in both bleomycin and Tsk-1 murine models. Moreover, Thy-1 regulated key pathogenic pathways involved in fibrosis including inflammation, myofibroblast differentiation, apoptosis and multiple additional canonical fibrotic pathways. Therefore, while Thy-1 deficiency leads to exacerbated lung fibrosis, in skin it is protective. Moreover, Thy-1 may serve as a longitudinal marker to assess skin fibrosis.
Authors
Roberta G. Marangoni, Poulami Datta, Ananta Paine, Stacey Duemmel, Marc A. Nuzzo, Laura Sherwood, John Varga, Christopher Ritchlin, Benjamin D. Korman
Abstract
The kidney contains a population of resident macrophages from birth that expands as it grows and forms a contiguous network throughout the tissue. Kidney resident macrophages (KRMs) are important in homeostasis and the response to acute kidney injury (AKI). While the kidney contains many microenvironments, it is unknown whether KRMs are a heterogeneous population differentiated by function and location. We combined single-cell RNA sequencing (scRNAseq), spatial transcriptomics, flow cytometry, and immunofluorescence imaging to localize, characterize, and validate KRM populations during quiescence and following 19 minutes of bilateral ischemic kidney injury. scRNAseq and spatial transcriptomics revealed seven distinct KRM subpopulations, which are organized into zones corresponding to regions of the nephron. Each subpopulation was identifiable by a unique transcriptomic signature suggesting distinct functions. Specific protein markers were identified for two clusters allowing analysis by flow cytometry or immunofluorescence imaging. Following injury, the original localization of each subpopulation is lost, either from changing locations or transcriptomic signatures. The original spatial distribution of KRMs is not fully restored for at least 28 days post-injury. The change in KRM localization confirms a long hypothesized dysregulation of the local immune system following acute injury and may explain the increased risk for chronic kidney disease.
Authors
Matthew D. Cheung, Elise N. Erman, Kyle H. Moore, Jeremie M.P. Lever, Zhang Li, Jennifer R. LaFontaine, Gelare Ghajar-Rahimi, Shanrun Liu, Zhengqin Yang, Rafay Karim, Bradley K. Yoder, Anupam Agarwal, James F. George
Abstract
T cell receptor (TCR) sequences are exceptionally diverse and can now be comprehensively measured with next generation sequencing technologies. However, a thorough investigation of longitudinal TCR repertoires throughout childhood in health and during development of a common childhood disease, type 1 diabetes (T1D), has not been undertaken. Here, we deep-sequenced the TCR beta chain (TCRβ) repertoires from longitudinal peripheral blood DNA samples at four time points beginning early in life (median age of 1.4 years) from children that progressed to T1D (n=29) and age/sex-matched islet autoantibody negative controls (n=25). From 53 million TCRβ sequences, we show that the repertoire is extraordinarily diverse early in life and narrows with age independent of disease. We demonstrate the ability to identify specific TCR sequences, including those known to recognize influenza A and separately those specific for insulin and its precursor, preproinsulin. Insulin-reactive TCRβ sequences are more common and frequent in number as the disease progressed in those who developed T1D compared to genetically at-risk non-diabetic children, which was not the case for influenza-reactive sequences. As an independent validation, we sequenced and analyzed TCRβ repertoires from a cohort of new-onset T1D patients (n=143), identifying the same preproinsulin-reactive TCRs. These results demonstrate an enrichment of preproinsulin-reactive TCR sequences during the progression to T1D, highlighting the importance of using disease-relevant TCR sequences as powerful biomarkers in autoimmune disorders.
Authors
Angela M. Mitchell, Erin E. Baschal, Kristen A. McDaniel, Kimber M. Simmons, Laura Pyle, Kathleen Waugh, Andrea K. Steck, Liping Yu, Peter A. Gottlieb, Marian J. Rewers, Maki Nakayama, Aaron W. Michels
Abstract
New strategies that augment T-cell responses are required to broaden the therapeutic arsenal against cancer. CD96, TIGIT and CD226 are receptors that bind to a communal ligand, CD155, and transduce either inhibitory or activating signals. Whereas the function of TIGIT and CD226 is established, the role of CD96 remains ambiguous. Using a panel of engineered antibodies, we discovered that the T-cell stimulatory activity of anti-CD96 antibodies requires antibody crosslinking and is potentiated by Fc-gamma receptors. Thus, soluble ‘Fc silent’ anti-CD96 antibodies failed to stimulate human T cells, whereas the same antibodies were stimulatory after coating onto plastic surfaces. Remarkably, the activity of soluble anti-CD96 antibodies was reinstated by engineering the Fc domain to a human IgG1 isotype and was dependent on antibody trans-crosslinking by Fc-γRI. In contrast, neither human IgG2 nor variants with increased Fc-γ receptor IIB binding possessed stimulatory activity. Anti-CD96 antibodies acted directly on T cells and augmented gene expression networks associated with T-cell activation, leading to proliferation, cytokine secretion and resistance to regulatory T-cell suppression. Furthermore, CD96 expression correlated with survival in HPV+ head and neck squamous cell carcinoma and its crosslinking activated tumor-infiltrating T cells, thus highlighting the potential of anti-CD96 antibodies in cancer immunotherapy.
Authors
Anne Rogel, Fathima M. Ibrahim, Stephen M. Thirdborough, Florence Renart-Depontieu, Charles N. Birts, Sarah L. Buchan, Xavier Preville, Emma V. King, Aymen Al-Shamkhani
Abstract
Celiac disease is an immune-mediated intestinal disorder that results from loss of oral tolerance (LOT) to dietary gluten. Reovirus elicits inflammatory Th1 cells and suppresses Treg responses to dietary antigen in a strain-dependent manner. Strain type 1 Lang (T1L) breaks oral tolerance, while strain type 3 Dearing reassortant virus (T3D-RV) does not. We discovered that intestinal infection by T1L in mice leads to the recruitment and activation of NK cells in mesenteric lymph nodes (MLNs) in a type I IFN–dependent manner. Once activated following infection, NK cells produce type II IFN and contribute to IFN-stimulated gene expression in the MLNs, which in turn induces inflammatory DC and T cell responses. Immune depletion of NK cells impairs T1L-induced LOT to newly introduced food antigen. These studies indicate that NK cells modulate the response to dietary antigen in the presence of a viral infection.
Authors
Pamela H. Brigleb, Elaine Kouame, Kay L. Fiske, Gwen M. Taylor, Kelly Urbanek, Luzmariel Medina Sanchez, Reinhard Hinterleitner, Bana Jabri, Terence S. Dermody
Abstract
Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. One of every 4 preterm neonates is born to a mother with intra-amniotic inflammation driven by invading bacteria. However, the molecular mechanisms underlying this hostile immune response remain unclear. Here, we used a translationally relevant model of preterm birth in Nlrp3-deficient and -sufficient pregnant mice to identify what we believe is a previously unknown dual role for the NLRP3 pathway in the fetal and maternal signaling required for the premature onset of the labor cascade leading to fetal injury and neonatal death. Specifically, the NLRP3 sensor molecule and/or inflammasome is essential for triggering intra-amniotic and decidual inflammation, fetal membrane activation, uterine contractility, and cervical dilation. NLRP3 also regulates the functional status of neutrophils and macrophages in the uterus and decidua, without altering their influx, as well as maternal systemic inflammation. Finally, both embryo transfer experimentation and heterozygous mating systems provided mechanistic evidence showing that NLRP3 signaling in both the fetus and the mother is required for the premature activation of the labor cascade. These data provide insights into the mechanisms of fetal-maternal dialog in the syndrome of preterm labor and indicate that targeting the NLRP3 pathway could prevent adverse perinatal outcomes.
Authors
Kenichiro Motomura, Roberto Romero, Jose Galaz, Li Tao, Valeria Garcia-Flores, Yi Xu, Bogdan Done, Marcia Arenas-Hernandez, Derek Miller, Pedro Gutierrez-Contreras, Marcelo Farias-Jofre, Siddhesh Aras, Lawrence I. Grossman, Adi L. Tarca, Nardhy Gomez-Lopez
Abstract
Lentiviral vector-based dendritic cell vaccines induce protective T cell responses against viral infection and cancer in animal models. In this study, we tested whether preventative and therapeutic vaccination could be achieved by direct injection of antigen expressing lentiviral vector, obviating the need for ex vivo transduction of dendritic cells. Injected lentiviral vector preferentially transduced splenic dendritic cells and resulted in long-term expression. Injection of a lentiviral vector encoding an MHC class I restricted T cell epitope of LCMV and CD40L induced an antigen-specific cytolytic CD8+ T lymphocyte response that protected the mice from infection. The injection of chronically infected mice with a lentiviral vector encoding LCMV MHC class I and II T cell epitopes and a soluble PD-1 microbody rapidly cleared the virus. Vaccination by direct injection of lentiviral vector was more effective in SAMHD1 knock-out mice, suggesting that lentiviral vectors containing Vpx, a lentiviral protein that increases the efficiency of dendritic cell transduction by inducing the degradation of SAMHD1, would be an effective strategy for the treatment of chronic disease in humans.
Authors
Takuya Tada, Thomas D. Norton, Rebecca Leibowitz, Nathaniel R. Landau
Abstract
B-lymphocytes have long been recognized for their critical contributions to adaptive immunity, providing defense against pathogens through cognate antigen presentation to T cells and antibody production. More recently appreciated is that B cells are also integral in securing self-tolerance; this has led to interest in their therapeutic application to down-regulate unwanted immune responses such as transplant rejection. In this study, we found that PMA and ionomycin-activated mouse B cells acquire regulatory properties following stimulation through Toll-like receptor (TLR)4/TLR9 receptors (Bregs-TLR). Bregs-TLR efficiently inhibited T cell proliferation in vitro and prevented allograft rejection. Unlike most reported Breg activities, the inhibition of alloimmune responses by Bregs-TLR relied on the expression of TGF-βand not IL-10. In vivo, Bregs-TLR interrupted donor-specific T cell expansion and induced regulatory T cells in a TGF-β dependent manner. RNA-seq analyses corroborated the involvement of TGF-β pathways in Breg-TLR function, identified potential gene pathways implicated in preventing graft rejection, and suggested new targets to foster Breg regulation.
Authors
Kang Mi Lee, Qiang Fu, Guoli Huai, Kevin Deng, Ji Lei, Lisa Kojima, Divyansh Agarwal, Peter Van Galen, Shoko Kimura, Naoki Tanimine, Laura Washburn, Heidi Yeh, Ali Naji, Charles G. Rickert, Christian LeGuern, James F. Markmann
Abstract
Plasmacytoid dendritic cells (pDCs) perform dual proinflammatory and immunosuppressive roles. We recently reported the potential of pDC therapy for treatment of intractable acute liver failure. However, establishment of efficient methods to deliver pDCs to the liver is essential for future clinical therapeutic applications. The present study demonstrates a higher abundance of liver and peripheral blood pDCs in mice lacking the C-C motif chemokine receptor 9 (CCR9), a pDC gut-homing receptor, than that in wild-type (WT) mice. Adoptive pDC transfer resulted in a higher efficiency of Ccr9-/- pDC migration to the liver than that to the original target organ, the small intestine, compared with that of WT pDCs. Further, Ccr9-/- pDCs consistently migrated efficiently to the concanavalin A-induced inflamed liver, and exerted a more effective immunosuppressive effect, resulting in better protection against acute liver inflammation than that demonstrated by WT pDCs. These findings highlight the therapeutic potential of the manipulation of CCR9 axis as a novel approach to improve migration of immunosuppressive pDCs to the liver in order to exploit their beneficial effects in acute liver disease.
Authors
Yuzo Koda, Nobuhiro Nakamoto, Po-Sung Chu, Toshiaki Teratani, Akihisa Ueno, Takeru Amiya, Nobuhito Taniki, Sayako Chiba, Kentaro Miyamoto, Michiie Sakamoto, Takanori Kanai
Abstract
The immune factors associated with impaired SARS-CoV-2 vaccine response in the elderly are mostly unknown. We studied >60 and <60 years old people vaccinated with SARS-CoV-2 BNT162b2 mRNA before and after the first and second dose. Aging was associated with a lower anti-RBD IgG levels and a decreased magnitude and polyfunctionality of SARS-CoV-2 specific T cell response. The dramatic decrease in thymic function in aged people with >60 years of age, which fueled alteration in T cell homeostasis, and lower CD161+ T cell levels were associated with decreased T cell response two months after vaccination. Additionally, a deficient dendritic cell (DC) homing, activation and Toll like receptor (TLR)-mediated function, along with a proinflammatory functional profile in monocytes, were observed in the >60 years old group, which was also related to lower specific T cell response after vaccination. These findings might be relevant for the improvement of the current vaccination strategies and for the development of new vaccine prototypes.
Authors
Joana Vitallé, Alberto Pérez-Gómez, Francisco José Ostos, Carmen Gasca-Capote, Maria Reyes Jiménez-Leon, Sara Bachiller, Inmaculada Rivas-Jeremías, Maria del Mar Silva-Sánchez, Anabel M. Ruiz-Mateos, María Ángeles Martín-Sánchez, Luis Fernando López-Cortes, Mohammed Rafii El Idrissi Benhnia, Ezequiel Ruiz-Mateos
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