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Nature Reviews. Microbiology Feb 2023Lassa virus (LASV) is endemic in the rodent populations of Sierra Leone, Nigeria and other countries in West Africa. Spillover to humans occurs frequently and results in... (Review)
Review
Lassa virus (LASV) is endemic in the rodent populations of Sierra Leone, Nigeria and other countries in West Africa. Spillover to humans occurs frequently and results in Lassa fever, a viral haemorrhagic fever (VHF) associated with a high case fatality rate. Despite advances, fundamental gaps in knowledge of the immunology, epidemiology, ecology and pathogenesis of Lassa fever persist. More frequent outbreaks, the potential for further geographic expansion of Mastomys natalensis and other rodent reservoirs, the ease of procurement and possible use and weaponization of LASV, the frequent importation of LASV to North America and Europe, and the emergence of novel LASV strains in densely populated West Africa have driven new initiatives to develop countermeasures for LASV. Although promising candidates are being evaluated, as yet there are no approved vaccines or therapeutics for human use. This Review discusses the virology of LASV, the clinical course of Lassa fever and the progress towards developing medical countermeasures.
Topics: Humans; Lassa Fever; Lassa virus; Africa, Western; Viral Vaccines
PubMed: 36097163
DOI: 10.1038/s41579-022-00789-8 -
Immunity Nov 2022The surface of the central nervous system (CNS) is protected by the meninges, which contain a dense network of meningeal macrophages (MMs). Here, we examined the role of...
The surface of the central nervous system (CNS) is protected by the meninges, which contain a dense network of meningeal macrophages (MMs). Here, we examined the role of tissue-resident MM in viral infection. MHC-II MM were abundant neonatally, whereas MHC-II MM appeared over time. These barrier macrophages differentially responded to in vivo peripheral challenges such as LPS, SARS-CoV-2, and lymphocytic choriomeningitis virus (LCMV). Peripheral LCMV infection, which was asymptomatic, led to a transient infection and activation of the meninges. Mice lacking macrophages but conserving brain microglia, or mice bearing macrophage-specific deletion of Stat1 or Ifnar, exhibited extensive viral spread into the CNS. Transcranial pharmacological depletion strategies targeting MM locally resulted in several areas of the meninges becoming infected and fatal meningitis. Low numbers of MHC-II MM, which is seen upon LPS challenge or in neonates, corelated with higher viral load upon infection. Thus, MMs protect against viral infection and may present targets for therapeutic manipulation.
Topics: Animals; Mice; Lipopolysaccharides; Mice, Inbred C57BL; SARS-CoV-2; COVID-19; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Macrophages; Meninges
PubMed: 36323311
DOI: 10.1016/j.immuni.2022.10.005 -
Nature Immunology Nov 2022Naïve CD8 T cells can differentiate into effector (T), memory (T) or exhausted (T) T cells. These developmental pathways are associated with distinct transcriptional...
Naïve CD8 T cells can differentiate into effector (T), memory (T) or exhausted (T) T cells. These developmental pathways are associated with distinct transcriptional and epigenetic changes that endow cells with different functional capacities and therefore therapeutic potential. The molecular circuitry underlying these developmental trajectories and the extent of heterogeneity within T, T and T populations remain poorly understood. Here, we used the lymphocytic choriomeningitis virus model of acute-resolving and chronic infection to address these gaps by applying longitudinal single-cell RNA-sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analyses. These analyses uncovered new subsets, including a subpopulation of T cells expressing natural killer cell-associated genes that is dependent on the transcription factor Zeb2, as well as multiple distinct TCF-1 stem/progenitor-like subsets in acute and chronic infection. These data also revealed insights into the reshaping of T subsets following programmed death 1 (PD-1) pathway blockade and identified a key role for the cell stress regulator, Btg1, in establishing the T population. Finally, these results highlighted how the same biological circuits such as cytotoxicity or stem/progenitor pathways can be used by CD8 T cell subsets with highly divergent underlying chromatin landscapes generated during different infections.
Topics: Humans; CD8-Positive T-Lymphocytes; Transcriptome; Lymphocytic choriomeningitis virus; Epigenesis, Genetic; Chromatin; Lymphocytic Choriomeningitis
PubMed: 36271148
DOI: 10.1038/s41590-022-01338-4 -
Nature Immunology Mar 2021During chronic infection and cancer, a self-renewing CD8 T cell subset maintains long-term immunity and is critical to the effectiveness of immunotherapy. These...
During chronic infection and cancer, a self-renewing CD8 T cell subset maintains long-term immunity and is critical to the effectiveness of immunotherapy. These stem-like CD8 T cells diverge from other CD8 subsets early after chronic viral infection. However, pathways guarding stem-like CD8 T cells against terminal exhaustion remain unclear. Here, we show that the gene encoding transcriptional repressor BACH2 is transcriptionally and epigenetically active in stem-like CD8 T cells but not terminally exhausted cells early after infection. BACH2 overexpression enforced stem-like cell fate, whereas BACH2 deficiency impaired stem-like CD8 T cell differentiation. Single-cell transcriptomic and epigenomic approaches revealed that BACH2 established the transcriptional and epigenetic programs of stem-like CD8 T cells. In addition, BACH2 suppressed the molecular program driving terminal exhaustion through transcriptional repression and epigenetic silencing. Thus, our study reveals a new pathway that enforces commitment to stem-like CD8 lineage and prevents an alternative terminally exhausted cell fate.
Topics: Animals; Arenaviridae Infections; Basic-Leucine Zipper Transcription Factors; CD8-Positive T-Lymphocytes; Cell Differentiation; Cell Lineage; Cells, Cultured; Chronic Disease; Disease Models, Animal; Epigenesis, Genetic; Host-Pathogen Interactions; Lymphocytic choriomeningitis virus; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Precursor Cells, T-Lymphoid; Signal Transduction; Transcription, Genetic; Mice
PubMed: 33574619
DOI: 10.1038/s41590-021-00868-7 -
Trends in Immunology Apr 2023Reinvigorating the function of exhausted CD8 T cells during chronic viral infection and cancer is a major goal of current immunotherapy regimens. Here, we discuss recent... (Review)
Review
Reinvigorating the function of exhausted CD8 T cells during chronic viral infection and cancer is a major goal of current immunotherapy regimens. Here, we discuss recent advances in our understanding of exhausted CD8 T cell heterogeneity as well as the potential differentiation trajectories that exhausted T cells follow during chronic infection and/or cancer. We highlight surmounting evidence suggesting that some T cell clones are divergent in nature and can develop into either terminally differentiated effector or exhausted CD8 T cells. Lastly, we consider the potential therapeutic implications of such a bifurcation model of CD8 T cell differentiation, including the intriguing hypothesis that redirecting progenitor CD8 T cell differentiation along an effector pathway may serve as a novel approach to mitigate T cell exhaustion.
Topics: Humans; CD8-Positive T-Lymphocytes; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Cell Differentiation; Neoplasms
PubMed: 36907685
DOI: 10.1016/j.it.2023.02.006 -
Molecular Cell Jun 2021CD8 T cells play an essential role in defense against viral and bacterial infections and in tumor immunity. Deciphering T cell loss of functionality is complicated by...
CD8 T cells play an essential role in defense against viral and bacterial infections and in tumor immunity. Deciphering T cell loss of functionality is complicated by the conspicuous heterogeneity of CD8 T cell states described across experimental and clinical settings. By carrying out a unified analysis of over 300 assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) experiments from 12 studies of CD8 T cells in cancer and infection, we defined a shared differentiation trajectory toward dysfunction and its underlying transcriptional drivers and revealed a universal early bifurcation of functional and dysfunctional T cell states across models. Experimental dissection of acute and chronic viral infection using single-cell ATAC (scATAC)-seq and allele-specific single-cell RNA (scRNA)-seq identified state-specific drivers and captured the emergence of similar TCF1 progenitor-like populations at an early branch point, at which functional and dysfunctional T cells diverge. Our atlas of CD8 T cell states will facilitate mechanistic studies of T cell immunity and translational efforts.
Topics: Acute Disease; Atlases as Topic; CD8-Positive T-Lymphocytes; Chromatin; Chronic Disease; Epigenesis, Genetic; Gene Expression Profiling; Gene Regulatory Networks; High-Throughput Nucleotide Sequencing; Humans; Immunity, Cellular; Lymphocyte Activation; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Neoplasms; Principal Component Analysis; Single-Cell Analysis; Transcription Factors; Transcription, Genetic; Transposases
PubMed: 33891860
DOI: 10.1016/j.molcel.2021.03.045 -
Nature Immunology Aug 2021During chronic viral infection, CD8 T cells develop into three major phenotypically and functionally distinct subsets: Ly108TCF-1 progenitors, Ly108CXCR1 terminally...
During chronic viral infection, CD8 T cells develop into three major phenotypically and functionally distinct subsets: Ly108TCF-1 progenitors, Ly108CXCR1 terminally exhausted cells and the recently identified CXCR1 cytotoxic effector cells. Nevertheless, how CXCR1 effector cell differentiation is transcriptionally and epigenetically regulated remains elusive. Here, we identify distinct gene regulatory networks and epigenetic landscapes underpinning the formation of these subsets. Notably, our data demonstrate that CXCR1 effector cells bear a striking similarity to short-lived effector cells during acute infection. Genetic deletion of Tbx21 significantly diminished formation of the CXCR1 subset. Importantly, we further identify a previously unappreciated role for the transcription factor BATF in maintaining a permissive chromatin structure that allows the transition from TCF-1 progenitors to CXCR1 effector cells. BATF directly bound to regulatory regions near Tbx21 and Klf2, modulating their enhancer accessibility to facilitate the transition. These mechanistic insights can potentially be harnessed to overcome T cell exhaustion during chronic infection and cancer.
Topics: Animals; Antigens, Ly; Basic-Leucine Zipper Transcription Factors; CD8-Positive T-Lymphocytes; CX3C Chemokine Receptor 1; Cell Differentiation; Cell Line; Female; Hepatocyte Nuclear Factor 1-alpha; Kruppel-Like Transcription Factors; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; T-Box Domain Proteins; T-Lymphocyte Subsets
PubMed: 34282329
DOI: 10.1038/s41590-021-00965-7 -
Immunity Feb 2022TbetCD11c B cells arise during type 1 pathogen challenge, aging, and autoimmunity in mice and humans. Here, we examined the developmental requirements of this B cell...
TbetCD11c B cells arise during type 1 pathogen challenge, aging, and autoimmunity in mice and humans. Here, we examined the developmental requirements of this B cell subset. In acute infection, T follicular helper (Tfh) cells, but not Th1 cells, drove TbetCD11c B cell generation through proximal delivery of help. TbetCD11c B cells developed prior to germinal center (GC) formation, exhibiting phenotypic and transcriptional profiles distinct from GC B cells. Fate tracking revealed that most TbetCD11c B cells developed independently of GC entry and cell-intrinsic Bcl6 expression. TbetCD11c and GC B cells exhibited minimal repertoire overlap, indicating distinct developmental pathways. As the infection resolved, TbetCD11c B cells localized to the marginal zone where splenic retention depended on integrins LFA-1 and VLA-4, forming a competitive memory subset that contributed to antibody production and secondary GC seeding upon rechallenge. Therefore, TbetCD11c B cells comprise a GC-independent memory subset capable of rapid and robust recall responses.
Topics: Animals; Antibodies, Viral; B-Lymphocytes; CD11 Antigens; Cell Differentiation; Germinal Center; Alphainfluenzavirus; Integrins; Lymphocyte Subsets; Lymphocytic choriomeningitis virus; Memory B Cells; Mice; Spleen; T Follicular Helper Cells; T-Box Domain Proteins; Virus Diseases
PubMed: 35090581
DOI: 10.1016/j.immuni.2022.01.002 -
The Journal of Experimental Medicine Oct 2022Recent studies have defined a novel population of PD-1+ TCF-1+ stem-like CD8 T cells in chronic infections and cancer. These quiescent cells reside in lymphoid tissues,...
Recent studies have defined a novel population of PD-1+ TCF-1+ stem-like CD8 T cells in chronic infections and cancer. These quiescent cells reside in lymphoid tissues, are critical for maintaining the CD8 T cell response under conditions of persistent antigen, and provide the proliferative burst after PD-1 blockade. Here we examined the role of TGF-β in regulating the differentiation of virus-specific CD8 T cells during chronic LCMV infection of mice. We found that TGF-β signaling was not essential for the generation of the stem-like CD8 T cells but was critical for maintaining the stem-like state and quiescence of these cells. TGF-β regulated the unique transcriptional program of the stem-like subset, including upregulation of inhibitory receptors specifically expressed on these cells. TGF-β also promoted the terminal differentiation of exhausted CD8 T cells by suppressing the effector-associated program. Together, the absence of TGF-β signaling resulted in significantly increased accumulation of effector-like CD8 T cells. These findings have implications for immunotherapies in general and especially for T cell therapy against chronic infections and cancer.
Topics: Animals; CD8-Positive T-Lymphocytes; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Mice; Neoplasms; Persistent Infection; Programmed Cell Death 1 Receptor; Transforming Growth Factor beta
PubMed: 35980386
DOI: 10.1084/jem.20211574 -
Nature Immunology Oct 2019CD8 T cell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6 progenitor exhausted and Tim-3...
CD8 T cell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6 progenitor exhausted and Tim-3 terminally exhausted subpopulations through unknown mechanisms. Here we establish the phosphatase PTPN2 as a new regulator of the differentiation of the terminally exhausted subpopulation that functions by attenuating type 1 interferon signaling. Deletion of Ptpn2 in CD8 T cells increased the generation, proliferative capacity and cytotoxicity of Tim-3 cells without altering Slamf6 numbers during lymphocytic choriomeningitis virus clone 13 infection. Likewise, Ptpn2 deletion in CD8 T cells enhanced Tim-3 anti-tumor responses and improved tumor control. Deletion of Ptpn2 throughout the immune system resulted in MC38 tumor clearance and improved programmed cell death-1 checkpoint blockade responses to B16 tumors. Our results indicate that increasing the number of cytotoxic Tim-3CD8 T cells can promote effective anti-tumor immunity and implicate PTPN2 in immune cells as an attractive cancer immunotherapy target.
Topics: Adenocarcinoma; Animals; CD8-Positive T-Lymphocytes; Cellular Senescence; Colonic Neoplasms; Cytotoxicity, Immunologic; Female; Hepatitis A Virus Cellular Receptor 2; Immune Tolerance; Immunotherapy; Interferon Type I; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Lymphoid Progenitor Cells; Male; Melanoma; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Transgenic; Protein Tyrosine Phosphatase, Non-Receptor Type 2; Signal Transduction; Signaling Lymphocytic Activation Molecule Family; Skin Neoplasms
PubMed: 31527834
DOI: 10.1038/s41590-019-0480-4