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Nature Immunology Oct 2023Persistent exposure to antigen during chronic infection or cancer renders T cells dysfunctional. The molecular mechanisms regulating this state of exhaustion are thought...
Persistent exposure to antigen during chronic infection or cancer renders T cells dysfunctional. The molecular mechanisms regulating this state of exhaustion are thought to be common in infection and cancer, despite obvious differences in their microenvironments. Here we found that NFAT5, an NFAT family transcription factor that lacks an AP-1 docking site, was highly expressed in exhausted CD8 T cells in the context of chronic infections and tumors but was selectively required in tumor-induced CD8 T cell exhaustion. Overexpression of NFAT5 in CD8 T cells reduced tumor control, while deletion of NFAT5 improved tumor control by promoting the accumulation of tumor-specific CD8 T cells that had reduced expression of the exhaustion-associated proteins TOX and PD-1 and produced more cytokines, such as IFNɣ and TNF, than cells with wild-type levels of NFAT5, specifically in the precursor exhausted PD-1TCF1TIM-3CD8 T cell population. NFAT5 did not promote T cell exhaustion during chronic infection with clone 13 of lymphocytic choriomeningitis virus. Expression of NFAT5 was induced by TCR triggering, but its transcriptional activity was specific to the tumor microenvironment and required hyperosmolarity. Thus, NFAT5 promoted the exhaustion of CD8 T cells in a tumor-selective fashion.
Topics: Humans; Lymphocytic Choriomeningitis; Transcription Factors; CD8-Positive T-Lymphocytes; T-Cell Exhaustion; Persistent Infection; Tumor Microenvironment; Programmed Cell Death 1 Receptor; Lymphocytic choriomeningitis virus; Neoplasms
PubMed: 37709986
DOI: 10.1038/s41590-023-01614-x -
Nature Mar 2024Immune cells rely on transient physical interactions with other immune and non-immune populations to regulate their function. To study these 'kiss-and-run' interactions...
Immune cells rely on transient physical interactions with other immune and non-immune populations to regulate their function. To study these 'kiss-and-run' interactions directly in vivo, we previously developed LIPSTIC (labelling immune partnerships by SorTagging intercellular contacts), an approach that uses enzymatic transfer of a labelled substrate between the molecular partners CD40L and CD40 to label interacting cells. Reliance on this pathway limited the use of LIPSTIC to measuring interactions between CD4 T helper cells and antigen-presenting cells, however. Here we report the development of a universal version of LIPSTIC (uLIPSTIC), which can record physical interactions both among immune cells and between immune and non-immune populations irrespective of the receptors and ligands involved. We show that uLIPSTIC can be used, among other things, to monitor the priming of CD8 T cells by dendritic cells, reveal the steady-state cellular partners of regulatory T cells and identify germinal centre-resident T follicular helper cells on the basis of their ability to interact cognately with germinal centre B cells. By coupling uLIPSTIC with single-cell transcriptomics, we build a catalogue of the immune populations that physically interact with intestinal epithelial cells at the steady state and profile the evolution of the interactome of lymphocytic choriomeningitis virus-specific CD8 T cells in multiple organs following systemic infection. Thus, uLIPSTIC provides a broadly useful technology for measuring and understanding cell-cell interactions across multiple biological systems.
Topics: CD8-Positive T-Lymphocytes; Cell Communication; Dendritic Cells; Ligands; T-Lymphocytes, Regulatory; T Follicular Helper Cells; B-Lymphocytes; Germinal Center; Single-Cell Gene Expression Analysis; Epithelial Cells; Intestinal Mucosa; Lymphocytic choriomeningitis virus; Lymphocytic Choriomeningitis; Organ Specificity
PubMed: 38448581
DOI: 10.1038/s41586-024-07134-4 -
Emerging Microbes & Infections Dec 2023Emerging zoonoses of wildlife origin caused by previously unknown agents are one of the most important challenges for human health. The Qinghai-Tibet Plateau represents...
Emerging zoonoses of wildlife origin caused by previously unknown agents are one of the most important challenges for human health. The Qinghai-Tibet Plateau represents a unique ecological niche with diverse wildlife that harbours several human pathogens and numerous previously uncharacterized pathogens. In this study, we identified and characterized a novel arenavirus (namely, plateau pika virus, PPV) from plateau pikas () on the Qinghai-Tibet Plateau by virome analysis. Isolated PPV strains could replicate in several mammalian cells. We further investigated PPV pathogenesis using animal models. PPV administered via an intraventricular route caused trembling and sudden death in IFNαβR mice, and pathological inflammatory lesions in brain tissue were observed. According to a retrospective serological survey in the geographical region where PPV was isolated, PPV-specific IgG antibodies were detected in 8 (2.4%) of 335 outpatients with available sera. Phylogenetic analyses revealed that this virus was clearly separated from previously reported New and Old World mammarenaviruses. Under the co-speciation framework, the estimated divergence time of PPV was 77-88 million years ago (MYA), earlier than that of OW and NW mammarenaviruses (26-34 MYA).
Topics: Animals; Humans; Mice; Arenaviridae; Phylogeny; Retrospective Studies; Tibet; Animals, Wild; Lagomorpha
PubMed: 36939609
DOI: 10.1080/22221751.2023.2192816 -
The Journal of Infectious Diseases Oct 2023Lassa virus (LASV), Junin virus (JUNV), and several other members of the Arenaviridae family are capable of zoonotic transfer to humans and induction of severe viral...
Lassa virus (LASV), Junin virus (JUNV), and several other members of the Arenaviridae family are capable of zoonotic transfer to humans and induction of severe viral hemorrhagic fevers. Despite the importance of arenaviruses as potential pandemic pathogens, numerous gaps exist in scientific knowledge pertaining to this diverse family, including gaps in understanding replication, immunosuppression, receptor usage, and elicitation of neutralizing antibody responses, that in turn complicates development of medical countermeasures. A further challenge to the development of medical countermeasures for arenaviruses is the requirement for use of animal models at high levels of biocontainment, where each model has distinct advantages and limitations depending on, availability of space, animals species-specific reagents, and most importantly the ability of the model to faithfully recapitulate human disease. Designation of LASV and JUNV as prototype pathogens can facilitate progress in addressing the public health challenges posed by members of this important virus family.
Topics: Animals; Humans; Arenaviridae; Virus Replication; Junin virus; Lassa virus; Models, Animal
PubMed: 37849403
DOI: 10.1093/infdis/jiac266 -
The Journal of General Virology Sep 2023is a family for ambisense RNA viruses with genomes of about 10.5 kb that infect mammals, snakes, and fish. The arenavirid genome consists of two or three...
is a family for ambisense RNA viruses with genomes of about 10.5 kb that infect mammals, snakes, and fish. The arenavirid genome consists of two or three single-stranded RNA segments and encodes a nucleoprotein (NP), a glycoprotein (GP) and a large (L) protein containing RNA-directed RNA polymerase (RdRP) domains; some arenavirids encode a zinc-binding protein (Z). This is a summary of the International Committee on Taxonomy of Viruses (ICTV) report on the family , which is available at www.ictv.global/report/arenaviridae.
Topics: Animals; Arenaviridae; Nucleoproteins; RNA; RNA-Dependent RNA Polymerase; Mammals
PubMed: 37698490
DOI: 10.1099/jgv.0.001891 -
Virulence Dec 2023
Topics: Humans; Arenaviridae; Viral Proteins; Arenaviridae Infections
PubMed: 37968871
DOI: 10.1080/21505594.2023.2279353 -
Proceedings of the National Academy of... Oct 2023CD8 T cells play an essential role in antitumor immunity and chronic viral infections. Recent findings have delineated the differentiation pathway of CD8 T cells in...
CD8 T cells play an essential role in antitumor immunity and chronic viral infections. Recent findings have delineated the differentiation pathway of CD8 T cells in accordance with the progenitor-progeny relationship of TCF1 stem-like and Tim-3TCF1 more differentiated T cells. Here, we investigated the characteristics of stem-like and differentiated CD8 T cells isolated from several murine tumor models and human lung cancer samples in terms of phenotypic and transcriptional features as well as their location compared to virus-specific CD8 T cells in the chronically lymphocytic choriomeningitis virus (LCMV)-infected mice. We found that CD8 tumor-infiltrating lymphocytes (TILs) in both murine and human tumors exhibited overall similar phenotypic and transcriptional characteristics compared to corresponding subsets in the spleen of chronically infected mice. Moreover, stem-like CD8 TILs exclusively responded and produced effector-like progeny CD8 T cells in vivo after antigenic restimulation, confirming their lineage relationship and the proliferative potential of stem-like CD8 TILs. Most importantly, similar to the preferential localization of PD-1 stem-like CD8 T cells in T cell zones of the spleen during chronic LCMV infection, we found that the PD-1 stem-like CD8 TILs in lung cancer samples are preferentially located not in the tumor parenchyma but in tertiary lymphoid structures (TLSs). The stem-like CD8 T cells are present in TLSs located within and at the periphery of the tumor, as well as in TLSs closely adjacent to the tumor parenchyma. These findings suggest that TLSs provide a protective niche to support the quiescence and maintenance of stem-like CD8 T cells in the tumor.
Topics: Humans; Animals; Mice; Lymphocytic Choriomeningitis; Programmed Cell Death 1 Receptor; CD8-Positive T-Lymphocytes; Lymphocytic choriomeningitis virus; Persistent Infection; Lung Neoplasms; Mice, Inbred C57BL
PubMed: 37782797
DOI: 10.1073/pnas.2221985120 -
Blood Dec 2023
Topics: Animals; Arenaviridae; Arenaviridae Infections; Hemorrhage; Macaca
PubMed: 38095923
DOI: 10.1182/blood.2023022303 -
Bioinformation 2024Iron, an essential constituent of cell metabolism, is transported intra-cellularly bound to the ubiquitous 76 kDa blood glycoprotein transferrin via the transferrin...
Iron, an essential constituent of cell metabolism, is transported intra-cellularly bound to the ubiquitous 76 kDa blood glycoprotein transferrin via the transferrin receptor, CD71. Because of its structure, CD71 facilitates the binding and penetration of a large variety of viruses into the host. Among which the hemorrhagic fever-causing New World mammarena viruses (family of single stranded ambisense segmented RNA Arenaviridae), the single stranded positive sense RNA hepatitis C virus, the single stranded negative sense segmented influenza A virus, the single stranded negative sense RNA rabies virus, the single stranded positive sense SARS-CoV2 and possibly many others. In this process, CD71 is associated with the target of the anti-proliferative antibody-1 (CD81) viral co-receptor. In light of the plethora of novel and ancient viruses and microbes emerging from melting eternal glacier ice and permafrost, it is timely and critical to define and characterize interventions, besides the soluble form of CD71 (sCD71), that can abrogate or minimize this novice non-canonical function of CD71.
PubMed: 38711995
DOI: 10.6026/973206300200208