Single cell analysis of host response to helminth infection reveals the clonal breadth, heterogeneity, and tissue-specific programming of the responding CD4+ T cell repertoire

Ivy K Brown, Nathan Dyjack, Mindy M Miller, Harsha Krovi, Cydney Rios, Rachel Woolaver, Laura Harmacek, Ting-Hui Tu, Brian P O’Connor, Thomas Danhorn, Brian Vestal, Laurent Gapin, Clemencia Pinilla, Max A Seibold, James Scott-Browne, Radleigh G Santos and R Lee Reinhardt

PLOS Pathogens, 2021, vol. 17, issue 6, 1-34

Abstract: The CD4+ T cell response is critical to host protection against helminth infection. How this response varies across different hosts and tissues remains an important gap in our understanding. Using IL-4-reporter mice to identify responding CD4+ T cells to Nippostrongylus brasiliensis infection, T cell receptor sequencing paired with novel clustering algorithms revealed a broadly reactive and clonally diverse CD4+ T cell response. While the most prevalent clones and clonotypes exhibited some tissue selectivity, most were observed to reside in both the lung and lung-draining lymph nodes. Antigen-reactivity of the broader repertoires was predicted to be shared across both tissues and individual mice. Transcriptome, trajectory, and chromatin accessibility analysis of lung and lymph-node repertoires revealed three unique but related populations of responding IL-4+ CD4+ T cells consistent with T follicular helper, T helper 2, and a transitional population sharing similarity with both populations. The shared antigen reactivity of lymph node and lung repertoires combined with the adoption of tissue-specific gene programs allows for the pairing of cellular and humoral responses critical to the orchestration of anti-helminth immunity.Author summary: Using various “omic” approaches, the CD4+ T cell receptor (TCR) repertoire was explored after primary helminth infection. Infection generated a broadly reactive and clonally diverse CD4+ T cell response with the most prevalent clonotypes and predicted antigen specificities residing in both the lung and lung-draining lymph nodes. Tissue-specific programming of responding CD4+ T cells directed the establishment of committed Tfh and Th2 cells, both critical for driving distinct hallmarks of type-2 inflammation. These datasets help to explore the diverse yet tissue-specific nature of anti-helminth immunity.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:plo:ppat00:1009602

DOI: 10.1371/journal.ppat.1009602

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