Host genes define the severity of inflammation and immunity but specific loci doing so are unknown. Here we show that TNFRSF13B variants which enhance defense against certain pathogens, also control immune-mediated injury of transplants, by regulating innate B cells’ functions. Analysis of TNFRSF13B in human kidney transplant recipients revealed that 33% of the subjects with antibody-mediated rejection (AMR) but less than 6% of those with stable graft function had TNFRSF13B missense mutations. To explore mechanisms underlying aggressive immune responses we investigated allo-immunity and rejection in mice. Cardiac allografts in Tnfrsf13b-mutant mice underwent early and severe AMR. The dominance and precocity of AMR in Tnfrsf13b-deficient mice was not caused by increased alloantibodies. Rather, Tnfrsf13b mutations decreased “natural” IgM and compromised complement regulation leading to complement deposition in allografted hearts and autogenous kidneys. Thus, wild type TNFRSF13B and Tnfrsf13b support innate B cell functions that limit complement-associated inflammation; in contrast, common variants of these genes, intensify inflammatory responses that help clear microbial infections but allow inadvertent tissue injury to ensue. The wide variation in inflammatory reactions associated with TNFRSF13B diversity suggests polymorphisms could underlie variation in host defense and explosive inflammatory responses that sometimes enhances morbidity associated with immune responses.
Mayara Garcia de Mattos Barbosa, Adam R. Lefferts, Daniel Huynh, Hui Liu, Yu Zhang, Beverly Fu, Jenna Barnes, Milagros Samaniego, Richard J. Bram, Raif Geha, Ariella Shikanov, Eline T. Luning Prak, Evan A. Farkash, Jeffrey L. Platt, Marilia Cascalho
Rationale. The importance of the adaptative T cell response in the control and resolution of viral infection has been well-established. However, the nature of T cell-mediated viral control mechanisms in life-threatening stages of COVID-19 has yet to be determined. Objective. The aim of the present study was to determine the function and phenotype of T cell populations associated with survival or death of COVID-19 patients under intensive care as a result of phenotypic and functional profiling by mass cytometry. Findings. Increased frequencies of circulating, polyfunctional, CD4+CXCR5+HLA-DR+ stem cell memory T cells (TSCM) and decreased proportions of Granzyme-B and Perforin-expressing effector memory T cells (TEM) were detected in recovered and deceased patients, respectively. The higher abundance of polyfunctional CD8+PD-L1+CXCR3+ T effector cells, CXCR5+HLA-DR+ TSCM, as well as anti-nucleocapsid (NC) cytokine-producing T cells permitted to differentiate between recovered and deceased patients. The results from a principal component analysis showed an imbalance in the T cell compartment allowed for the separation of recovered and deceased patients. The paucity of circulating CD8+PD-L1+CXCR3+ Teff-cells and NC-specific CD8+ T-cells accurately forecasts fatal disease outcome. Conclusion. This study provides insight into the nature of the T cell populations involved in the control of COVID-19 and therefor might impact T cell-based vaccine designs for this infectious disease.
Lucille Adam, Pierre Rosenbaum, Paul Quentric, Christophe Parizot, Olivia Bonduelle, Noëlline Guillou, Aurelien Corneau, Karim Dorgham, Makoto Miyara, Charles-Edouard Luyt, Amélie Guihot, Guy Gorochov, Christophe Combadière, Behazine Combadière
γδ T cell is a promising candidate cell in tumor immunotherapy. However, γδ T cells polarized to CD39+γδ Tregs upon colorectal cancer (CRC) induction and the underlying mechanism remains unclear. Here, we discovered that the frequency of CD39+γδ Tregs, which positively correlated with poor prognosis, was significantly higher in right-sided CRC (RSCRC) than in the left-sided CRC (LSCRC). Interestingly, CD39+γδ Tregs from RSCRC showed stronger immunosuppressive phenotype and function than LSCRC. Further, the quantitative mass spectrometry data showed that CD39+γδ Tregs polarization was related to the abnormal activation of the PLA2G4A/AA metabolic pathway in RSCRC. Using an in vitro co-culture system and an orthotopic murine model of CRC, we proved that the overexpression of Pla2g4a in CT26 cells induced CD39+γδ Tregs inhibiting the anti-tumor immune response. Finally, we found that the overall survival of the PLA2G4Ahigh group was significantly shortened compared to PLA2G4Alow RSCRC, while the survival of LSCRC was on the contrary. Collectively, RSCRC with abnormal PLA2G4A expression educates γδ T cells into CD39+γδ Tregs to promote tumor progression and metastasis. Our work highlights the interaction between cancer cells and immune cells by distinguishing the primary tumor site and deepens the understanding of tumor microenvironment and immunosuppression.
Yang Zhan, Lei Zheng, Jia Liu, Dongzhi Hu, Junfeng Wang, Kai Liu, Jiansheng Guo, Ti Zhang, Dalu Kong
Energy balance is controlled by interconnected brain regions in the hypothalamus, brain stem, cortex and limbic system. Gene expression signatures of these regions can help elucidate the pathophysiology underlying obesity. RNA sequencing was conducted on P56 C57BL/6NTac male mice and E14.5 C57BL/6NTac embryos punch-biopsies in 16 obesity-relevant brain regions. The expression of 190 known obesity-associated genes (monogenic, rare and low-frequency coding variants, genome-wide association studies (GWAS), syndromic) were analyzed in each anatomical region. Genes associated with these genetic categories of obesity had localized expression patterns across brain regions. Known monogenic obesity causal genes were highly enriched in the arcuate nucleus of the hypothalamus and developing hypothalamus. The obesity-associated genes clustered into distinct ‘modules’ of similar expression profile and these are distinct from expression ‘modules’ formed by similar analysis with genes known to be associated with other disease phenotypes (type 1 and type 2 diabetes, autism, breast cancer) in the same energy balance-relevant brain regions.
Maria Caterina De Rosa, Hannah J. Glover, George Stratigopoulos, Charles A. LeDuc, Qi Su, Yufeng Shen, Mark W. Sleeman, Wendy K. Chung, Rudolph L. Leibel, Judith Y. Altarejos, Claudia A. Doege
Type-2 dendritic cells (DC2s) comprise the majority of conventional DCs within most tumors; however, little is known about their ability to initiate and sustain anti-tumor immunity as most studies have focused on antigen cross-presenting Type-1 DCs (DC1s). Here we report that DC2 infiltration identified by analysis of multiple human cancer data sets showed a significant correlation with survival across multiple human cancers, with the benefit being seen in tumors resistant to cytotoxic T cell control. Characterization of DC subtype infiltration into an immunotherapy-resistant model of breast cancer revealed that impairment of DC1s through two unique models resulted in enhanced DC2 functionality and improved tumor control. Batf3-deficiency depleted intratumoral DC1s led to increased DC2 lymph node migration and CD4+ T cell activation. Enhancing DC2 stimulatory potential by genetic deletion of Hsp90b1 (encoding molecular chaperon GP96) led to a similar enhancement of T cell immunity and improved survival in a spontaneous breast cancer model. This data highlights the therapeutic and prognostic potential of DC2s within checkpoint blockade-resistant tumors.
Stephen Iwanowycz, Soo Ngoi, Yingqi Li, Megan Hill, Christopher Koivisto, Melodie Parrish, Beichu Guo, Zihai Li, Bei Liu
BACKGROUND. Naturally acquired immunity to malaria is incompletely understood. We used controlled human malaria infection (CHMI) to study the impact of past exposure to malaria in Kenyan adults in relation to infection with a non-Kenyan parasite strain. METHODS. We administered 3.2x103 aseptic, purified, cryopreserved Plasmodium falciparum (Pf) sporozoites (SPZ) [Sanaria® PfSPZ Challenge, NF54 West African strain] by direct venous inoculation and undertook clinical monitoring and serial quantitative PCR (qPCR) of the 18S ribosomal RNA gene. The study endpoint was met when either: parasitaemia reached ≥500 parasites/μl blood; clinically significant symptoms were seen; or at 21 days after inoculation. All volunteers received antimalarial drug treatment on meeting the endpoint. RESULTS. One hundred and sixty-one (161) volunteers underwent CHMI between Aug 4, 2016, and Feb 14, 2018. CHMI was well tolerated with no severe or serious adverse events. Nineteen volunteers (11.8%) were excluded from the analysis based on detection of antimalarial drugs above the minimal inhibitory concentration or parasites genotyped as non-NF54. Of the 142 volunteers who were eligible for analysis: 26 (18.3%) had febrile symptoms and were treated; 30 (21.1%) reached ≥500 parasites/μl and were treated; 53 (37.3%) had parasitaemia without meeting thresholds for treatment and; 33 (23.2%) remained qPCR negative. CONCLUSION. We find that past exposure to malaria, as evidenced by location of residence, in some Kenyan adults can completely suppress in vivo growth of a parasite strain originating from outside Kenya. TRAIL REGISTRATION. The study was registered on ClinicalTrials.gov (NCT02739763). FUNDING. Wellcome Trust
Melissa C. Kapulu, Patricia Njuguna, Mainga Hamaluba, Domtila Kimani, Joyce M. Ngoi, Janet Musembi, Omar Ngoto, Edward Otieno, Peter F. Billingsley
Neutrophil-mediated activation and injury of the endothelium play a role in the pathogenesis of diverse disease states ranging from autoimmunity to cancer to COVID-19. Neutralization of cationic proteins (such as neutrophil extracellular trap/NET-derived histones) with polyanionic compounds has been suggested as a potential strategy for protecting the endothelium from such insults. Here, we report that the FDA-approved polyanionic agent defibrotide (a pleotropic mixture of oligonucleotides) directly engages histones and thereby blocks their pathological effects on endothelium. In vitro, defibrotide counteracted endothelial cell activation and pyroptosis-mediated cell death, whether triggered by purified NETs or recombinant histone H4. In vivo, defibrotide stabilized the endothelium and protected against histone-accelerated inferior vena cava thrombosis in mice. Mechanistically, defibrotide demonstrated direct and tight binding to histone H4 as detected by both electrophoretic mobility shift assay and surface plasmon resonance. Taken together, these data provide insights into the potential role of polyanionic compounds in protecting the endothelium from thromboinflammation with potential implications for myriad NET- and histone-accelerated disease states.
Hui Shi, Alex A. Gandhi, Stephanie A. Smith, Qiuyu Wang, Diane Chiang, Srilakshmi Yalavarthi, Ramadan A. Ali, Chao Liu, Gautam Sule, Pei-Suen Tsou, Yu Zuo, Yogendra Kanthi, Evan A. Farkash, Jiandie D. Lin, James H. Morrissey, Jason S. Knight
The alpha ketoglutarate-dependent dioxygenase, prolyl-4-hydroxylase 3 (PHD3), is a Hypoxia-Inducible Factor (HIF) target that uses molecular oxygen to hydroxylate peptidyl prolyl residues. While PHD3 has been reported to influence cancer cell metabolism and liver insulin sensitivity, relatively little is known about effects of this highly conserved enzyme in insulin-secreting β-cells in vivo. Here, we show that deletion of PHD3 specifically in β-cells (βPHD3KO) is associated with impaired glucose homeostasis in mice fed high fat diet. In the early stages of dietary fat excess, βPHD3KO islets energetically rewire, leading to defects in the management of pyruvate fate and a shift from glycolysis to increased fatty acid oxidation (FAO). However, under more prolonged metabolic stress, this switch to preferential FAO in βPHD3KO islets is associated with impaired glucose-stimulated ATP/ADP rises, Ca2+ fluxes and insulin secretion. Thus, PHD3 might be a pivotal component of the β-cell glucose metabolism machinery in mice by suppressing the use of fatty acids as a primary fuel source during the early phases of metabolic stress.
Daniela Nasteska, Federica Cuozzo, Katrina Viloria, Elspeth M. Johnson, Alpesh Thakker, Rula Bany Bakar, Rebecca L. Westbrook, Jonathan P. Barlow, Monica Hoang, Jamie W. Joseph, Gareth G. Lavery, Ildem Akerman, James Cantley, Leanne Hodson, Daniel A. Tennant, David J. Hodson
A dynamically regulated microenvironment, which is mediated by crosstalks between adipocytes 2 and neighboring cells, is critical for adipose tissue homeostasis and function. However, information on 3 key molecules and/or signaling pathways regulating the crosstalks remains limited. In this study, we 4 identify adipocyte miR-182-5p as a crucial anti-obesity molecule that stimulates beige fat thermogenesis 5 by promoting the crosstalk between adipocytes and macrophages. miR-182-5p is highly enriched in 6 thermogenic adipocytes and its expression is markedly stimulated by cold exposure in mice. In contrast, 7 miR-182-5p expression is significantly reduced in adipose tissues of obese humans and mice. Knockout 8 of miR-185-5p decreased cold-induced beige fat thermogenesis whereas overexpression of miR-185-5p 9 increased beiging and thermogenesis in mice. Mechanistically, miR-182-5p promotes FGF21 expression 10 and secretion in adipocytes by suppressing Nr1d1 at 5'UTR, which in turn stimulates acetylcholine 11 synthesis and release in macrophages. Increased acetylcholine expression activates the nicotine 12 acetylcholine receptor in adipocytes, which stimulates PKA signaling and consequent thermogenic gene 13 expression. Our study reveals a key role of the miR-182-5p/FGF21/acetylcholine/acetylcholine receptor 14 axis that mediates the crosstalk between adipocytes and macrophages to promote beige fat 15 thermogenesis. Activation of the miR-182-5p-induced signaling pathway in adipose tissue may be an 16 effective approach to ameliorate obesity and associated metabolic diseases.
Wen Meng, Ting Xiao, Xiuci Liang, Jie Wen, Xinyi Peng, Jing Wang, Yi Zou, Jiahao Liu, Christie Bialowas, Hairong Luo, Yacheng Zhang, Bilian Liu, Jingjing Zhang, Fang Hu, Meilian Liu, Lily Q. Dong, Zhiguang Zhou, Feng Liu, Juli Bai
The syndrome of spontaneous preterm birth (sPTB) presents a challenge to mechanistic understanding, effective risk stratification, and management. Individual associations between sPTB, ethnicity, vaginal microbiota, metabolome and innate immune response are known, but not fully understood and knowledge has yet to impact clinical practice. Here we use multi-data type integration and composite statistical models to gain insight into sPTB risk by exploring the cervicovaginal environment of an ethnically heterogenous pregnant population (n=346 women; n=60 sPTB <37 weeks’ gestation, including n=27 sPTB <34 weeks). Analysis of cervicovaginal samples (10-15+6 weeks) identified novel interactions between risk of sPTB and microbiota, metabolite, and maternal host defense molecules. Statistical modelling identified a composite of metabolites (leucine, tyrosine, aspartate, lactate, betaine, acetate and Ca2+) associated with risk of sPTB <37 weeks (Area Under the Curve - AUC 0.752). A combination of glucose, aspartate, Ca2+ and Lactobacillus crispatus and L. acidophilus relative abundance, identified risk of early sPTB <34 weeks, (AUC 0.758); improved by ethnicity stratification (AUC 0.835). Increased relative abundance of L. acidophilus appeared protective against sPTB <34 weeks. By using cervicovaginal fluid samples, we demonstrate the potential of multi-datatype integration for developing composite models towards understanding the contribution of the vaginal environment to risk of sPTB.
Flavia Flaviani, Natasha L. Hezelgrave, Tokuwa Kanno, Erica M. Prosdocimi, Evonne Chin-Smith, Alexandra E. Ridout, Djuna K. von Maydell, Vikash Mistry, William G. Wade, Andrew H. Shennan, Konstantina Dimitrakopoulou, Paul T. Seed, Andrew James Mason, Rachel M. Tribe
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