Transgenic expression of a T cell epitope in Strongyloides ratti reveals that helminth-specific CD4+ T cells constitute both Th2 and Treg populations

Autor: James B. Lok, Jonathan R Kurtz, Thomas J. Nolan, Yun Wei, Annabel Ferguson, Bonnie Douglas, Xinshe Li, James B. McLachlan, Li-Yin Hung, Christopher F. Pastore, De’Broski R. Herbert
Jazyk: angličtina
Rok vydání: 2021
Předmět:
CD4-Positive T-Lymphocytes
0301 basic medicine
Life Cycles
Physiology
Epitopes
T-Lymphocyte
Biochemistry
T-Lymphocytes
Regulatory
Epitope
Animals
Genetically Modified
White Blood Cells
Mice
Medical Conditions
Larvae
0302 clinical medicine
Animal Cells
Immune Physiology
Medicine and Health Sciences
Biology (General)
Nematode Infections
Innate Immune System
biology
T Cells
Effector
Strongyloides ratti
Regulatory T cells
medicine.anatomical_structure
Helminth Infections
Strongyloidiasis
Cytokines
Cellular Types
Research Article
QH301-705.5
Immune Cells
T cell
Transgene
CD3
Immunology
Green Fluorescent Protein
Microbiology
03 medical and health sciences
Th2 Cells
Amphiregulin
Virology
Parasitic Diseases
Genetics
medicine
Animals
Molecular Biology
Blood Cells
Biology and Life Sciences
Proteins
Cell Biology
Molecular Development
RC581-607
Molecular biology
Fusion protein
Mice
Inbred C57BL
Luminescent Proteins
Disease Models
Animal
030104 developmental biology
Immune System
Antigens
Helminth
biology.protein
Parasitology
Immunologic diseases. Allergy
Developmental Biology
030215 immunology
Zdroj: PLoS Pathogens, Vol 17, Iss 7, p e1009709 (2021)
PLoS Pathogens
ISSN: 1553-7374
1553-7366
Popis: Helminths are distinct from microbial pathogens in both size and complexity, and are the likely evolutionary driving force for type 2 immunity. CD4+ helper T cells can both coordinate worm clearance and prevent immunopathology, but issues of T cell antigen specificity in the context of helminth-induced Th2 and T regulatory cell (Treg) responses have not been addressed. Herein, we generated a novel transgenic line of the gastrointestinal nematode Strongyloides ratti expressing the immunodominant CD4+ T cell epitope 2W1S as a fusion protein with green fluorescent protein (GFP) and FLAG peptide in order to track and study helminth-specific CD4+ T cells. C57BL/6 mice infected with this stable transgenic line (termed Hulk) underwent a dose-dependent expansion of activated CD44hiCD11ahi 2W1S-specific CD4+ T cells, preferentially in the lung parenchyma. Transcriptional profiling of 2W1S-specific CD4+ T cells isolated from mice infected with either Hulk or the enteric bacterial pathogen Salmonella expressing 2W1S revealed that pathogen context exerted a dominant influence over CD4+ T cell phenotype. Interestingly, Hulk-elicited 2W1S-specific CD4+ T cells exhibited both Th2 and Treg phenotypes and expressed high levels of the EGFR ligand amphiregulin, which differed greatly from the phenotype of 2W1S-specific CD4+ T cells elicited by 2W1S-expressing Salmonella. While immunization with 2W1S peptide did not enhance clearance of Hulk infection, immunization did increase total amphiregulin production as well as the number of amphiregulin-expressing CD3+ cells in the lung following Hulk infection. Altogether, this new model system elucidates effector as well as immunosuppressive and wound reparative roles of helminth-specific CD4+ T cells. This report establishes a new resource for studying the nature and function of helminth-specific T cells.
Author summary Intestinal parasitic helminths infect roughly one billion people worldwide, and there are currently no vaccines available for use in humans. In humans and experimental mouse infection models, CD4+ helper T cells that have differentiated into type 2 (Th2) effectors serve important roles in worm clearance and are considered essential for specific, long-lasting immunity. However, many helminth infections also drive expansion of regulatory T cells (Tregs) that can suppress inflammatory CD4+ T cell subsets. Whether Th2 and/or Treg subsets recognize helminth antigens is a question of great relevance to vaccine development, but no tools previously existed to identify and study endogenous helminth-specific CD4+ T cells. Here, we used transgenesis in the Strongyloides ratti model to engineer the first gastrointestinal (GI) nematode strain to express a tractable CD4+ T cell peptide epitope, 2W1S (Hulk). Our studies reveal that 2W1S-specific CD4+ T cells become both Th2s and Tregs in the lungs of infected mice and potentially serve protective and/or suppressive roles during Hulk infection. Development of this new model organism could be an important tool for studies designed to understand Th2 and Treg immunobiology, microenvironment-specific interactions, helminth-epitope processing/presentation, and T cell-dependent antibody responses.
Databáze: OpenAIRE
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