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- Title
Single cell analysis of host response to helminth infection reveals the clonal breadth, heterogeneity, and tissue-specific programming of the responding CD4<sup>+</sup> T cell repertoire.
- Authors
Brown, Ivy K.; Dyjack, Nathan; Miller, Mindy M.; Krovi, Harsha; Rios, Cydney; Woolaver, Rachel; Harmacek, Laura; Tu, Ting-Hui; O'Connor, Brian P.; Danhorn, Thomas; Vestal, Brian; Gapin, Laurent; Pinilla, Clemencia; Seibold, Max A.; Scott-Browne, James; Santos, Radleigh G.; Reinhardt, R. Lee
- 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.
- Subjects
CELL analysis; T cell receptors; T cells; HELMINTH hosts; HELMINTHIASIS; TH2 cells; LYMPH nodes; HETEROGENEITY
- Publication
PLoS Pathogens, 2021, Vol 17, Issue 6, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1009602