Type-2 CD8+ T-cell formation relies on interleukin-33 and is linked to asthma exacerbations

Esmee K. van der Ploeg, Lisette Krabbendam, Heleen Vroman, Menno van Nimwegen, Marjolein J.W. de Bruijn, Geertje M. de Boer, Ingrid M. Bergen, Mirjam Kool, Gerdien A. Tramper-Standers, Gert Jan Braunstahl, Danny Huylebroeck, Rudi W. Hendriks, Ralph Stadhouders*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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CD4+ T helper 2 (Th2) cells and group 2 innate lymphoid cells are considered the main producers of type-2 cytokines that fuel chronic airway inflammation in allergic asthma. However, CD8+ cytotoxic T (Tc) cells - critical for anti-viral defense - can also produce type-2 cytokines (referred to as ‘Tc2’ cells). The role of Tc cells in asthma and virus-induced disease exacerbations remains poorly understood, including which micro-environmental signals and cell types promote Tc2 cell formation. Here we show increased circulating Tc2 cell abundance in severe asthma patients, reaching peak levels during exacerbations and likely emerging from canonical IFNγ+ Tc cells through plasticity. Tc2 cell abundance is associated with increased disease burden, higher exacerbations rates and steroid insensitivity. Mouse models of asthma recapitulate the human disease by showing extensive type-2 skewing of lung Tc cells, which is controlled by conventional type-1 dendritic cells and IFNγ. Importantly, we demonstrate that the alarmin interleukin-33 (IL-33) critically promotes type-2 cytokine production by lung Tc cells in experimental allergic airway inflammation. Our data identify Tc cells as major producers of type-2 cytokines in severe asthma and during exacerbations that are remarkably sensitive to alterations in their inflammatory tissue micro-environment, with IL-33 emerging as an important regulator of Tc2 formation.

Original languageEnglish
Article number5137
JournalNature Communications
Issue number1
Publication statusPublished - 23 Aug 2023

Bibliographical note

Funding Information:
We thank all members from the Stadhouders and Hendriks laboratories for helpful discussions. R.W.H. is supported by Dutch Lung Foundation grant R.S. is supported by a Dutch Research Council Vidi grant (09150172010068), an Erasmus MC Fellowship, and a Dutch Lung Foundation Junior Investigator grant ( D.H. was supported by extra funds coordinated with the Erasmus MC Executive Board and joint BIG funding (between Erasmus University Rotterdam and Erasmus MC). H.V. is supported by a Dutch Lung Foundation grant (

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