Cytokines regulate the antigen-presenting characteristics of human circulating and tissue-resident intestinal ILCs

Anna Rao,Luca Mazzurana,Kumar P Tripathi,Ulrik Lindforss,Efthymia Kokkinou,Eduardo J Villablanca,Niklas K Björkström,Jenny Mjösberg,Hergen Spits,Mélanie Bruchard,Viktoria Konya,Anna Carrasco,Otto Strauss,Heinrich Schlums

doi:10.1038/s41467-020-15695-x

Abstract

ILCs and T helper cells have been shown to exert bi-directional regulation in mice. However, how crosstalk between ILCs and CD4+ T cells influences immune function in humans is unknown. Here we show that human intestinal ILCs co-localize with T cells in healthy and colorectal cancer tissue and display elevated HLA-DR expression in tumor and tumor-adjacent areas. Although mostly lacking co-stimulatory molecules ex vivo, intestinal and peripheral blood (PB) ILCs acquire antigen-presenting characteristics triggered by inflammasome-associated cytokines IL-1β and IL-18. IL-1β drives the expression of HLA-DR and co-stimulatory molecules on PB ILCs in an NF-κB-dependent manner, priming them as efficient inducers of cytomegalovirus-specific memory CD4+ T-cell responses. This effect is strongly inhibited by the anti-inflammatory cytokine TGF-β. Our results suggest that circulating and tissue-resident ILCs have the intrinsic capacity to respond to the immediate cytokine milieu and regulate local CD4+ T-cell responses, with potential implications for anti-tumor immunity and inflammation.

Highlights

innate lymphoid cells (ILCs) and T helper cells have been shown to exert bi-directional regulation in mice
We previously demonstrated the presence of a transcriptionally distinct HLA-DR+ CD127+ ILC3 subset in human tonsil based on single-cell RNA sequencing[14]
HLA-DR upregulation on ILCs was not clearly correlated to the cancer stage (Fig. 1b) but it was confined to the intestine, as we did not observe any differences in HLA-DR expression on peripheral blood (PB) ILCs between healthy donors and patients with colorectal cancer (CRC) (Supplementary Fig. 1f)

Summary

Introduction

ILCs and T helper cells have been shown to exert bi-directional regulation in mice. how crosstalk between ILCs and CD4+ T cells influences immune function in humans is unknown. IL-1β drives the expression of HLA-DR and co-stimulatory molecules on PB ILCs in an NF-κB-dependent manner, priming them as efficient inducers of cytomegalovirus-specific memory CD4+ T-cell responses. This effect is strongly inhibited by the anti-inflammatory cytokine TGF-β. IL-1β promotes the ability of PB ILCs to induce autologous cytomegalovirus (CMV)-specific memory CD4+ T-cell responses, demonstrating the functional capacity of ILCs for antigen uptake, processing and presentation. These properties are efficiently counteracted by TGF-β in PB ILC3-like cells. Better understanding of ILC-T-cell interactions and how they depend on the immediate cytokine microenvironment could be harnessed for improved immunomodulatory treatments

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Conclusion