Frontiers in Immunology (May 2022)

Fasciola hepatica Fatty Acid Binding Protein 1 Modulates T cell Polarization by Promoting Dendritic Cell Thrombospondin-1 Secretion Without Affecting Metabolic Homeostasis in Obese Mice

  • Anna Zawistowska-Deniziak,
  • Anna Zawistowska-Deniziak,
  • Anna Zawistowska-Deniziak,
  • Joost M. Lambooij,
  • Joost M. Lambooij,
  • Alicja Kalinowska,
  • Thiago A. Patente,
  • Thiago A. Patente,
  • Maciej Łapiński,
  • Hendrik J. P. van der Zande,
  • Hendrik J. P. van der Zande,
  • Katarzyna Basałaj,
  • Clarize M. de Korne,
  • Clarize M. de Korne,
  • Clarize M. de Korne,
  • Mathilde A. M. Chayé,
  • Mathilde A. M. Chayé,
  • Thomas A. Gasan,
  • Thomas A. Gasan,
  • Luke J. Norbury,
  • Luke J. Norbury,
  • Martin Giera,
  • Arnaud Zaldumbide,
  • Hermelijn H. Smits,
  • Hermelijn H. Smits,
  • Bruno Guigas,
  • Bruno Guigas

DOI
https://doi.org/10.3389/fimmu.2022.884663
Journal volume & issue
Vol. 13

Abstract

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BackgroundThe parasitic trematode Fasciola hepatica evades host immune defenses through secretion of various immunomodulatory molecules. Fatty Acid Binding Proteins (fhFABPs) are among the main excreted/secreted proteins and have been shown to display anti-inflammatory properties. However, little is currently known regarding their impact on dendritic cells (DCs) and their subsequent capacity to prime specific CD4+ T cell subsets.Methodology/Principal FindingsThe immunomodulatory effects of both native F. hepatica extracts and recombinant fhFABPs were assessed on monocyte-derived human DCs (moDCs) and the underlying mechanism was next investigated using various approaches, including DC-allogenic T cell co-culture and DC phenotyping through transcriptomic, proteomic and FACS analyses. We mainly showed that fhFABP1 induced a tolerogenic-like phenotype in LPS-stimulated moDCs characterized by a dose-dependent increase in the cell-surface tolerogenic marker CD103 and IL-10 secretion, while DC co-stimulatory markers were not affected. A significant decrease in secretion of the pro-inflammatory cytokines IL-12p70 and IL-6 was also observed. In addition, these effects were associated with an increase in both Th2-on-Th1 ratio and IL-10 secretion by CD4+ T cells following DC-T cell co-culture. RNA sequencing and targeted proteomic analyses identified thrombospondin-1 (TSP-1) as a non-canonical factor highly expressed and secreted by fhFABP1-primed moDCs. The effect of fhFABP1 on T cell skewing was abolished when using a TSP-1 blocking antibody during DC-T cell co-culture. Immunomodulation by helminth molecules has been linked to improved metabolic homeostasis during obesity. Although fhFABP1 injection in high-fat diet-fed obese mice induced a potent Th2 immune response in adipose tissue, it did not improved insulin sensitivity or glucose homeostasis.Conclusions/SignificanceWe show that fhFABP1 modulates T cell polarization, notably by promoting DC TSP-1 secretion in vitro, without affecting metabolic homeostasis in a mouse model of type 2 diabetes.

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