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

• Published in: PLoS pathogens Vol. 17; no. 7; p. e1009709
• Main Authors: Douglas, Bonnie, Wei, Yun, Li, Xinshe, Ferguson, Annabel, Hung, Li-Yin, Pastore, Christopher, Kurtz, Jonathan R, McLachlan, James B, Nolan, Thomas J, Lok, James, Herbert, De'Broski R
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.07.2021; Public Library of Science (PLoS)
• Subjects: Amphiregulin; Analysis; Animals; Animals, Genetically Modified; Antigens; Antigens, Helminth; Biology and Life Sciences; CD3 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Clearances; Context; Cytokines; Disease Models, Animal; Epitopes; Epitopes, T-Lymphocyte - genetics; Epitopes, T-Lymphocyte - immunology; Fluorescence; Fusion protein; Gene expression; Genetic aspects; Green fluorescent protein; Health aspects; Immunization; Immunodominance; Infections; Intestinal parasites; Lungs; Lymphatic system; Lymphocytes; Lymphocytes T; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Microorganisms; Nematodes; Parenchyma; Pathogens; Peptides; Phenotypes; Proteins; Salmonella; Small intestine; Strongyloides; Strongyloides ratti - immunology; Strongyloidiasis; Strongyloidiasis - immunology; T cells; T-Lymphocytes, Regulatory - immunology; Th2 Cells - immunology; Transcription; Transcription factors; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1009709

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.