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

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. [ABSTRACT FROM AUTHOR]