CD36 is a metabolic checkpoint for Th2 cell tissue residency during allergic airway inflammation

Krone, A.; Schreiber, S.; Jantz Naeem, N.; Sammt, A.; Dudeck, J.; Katsoulis Dimitriou, K.; Goihl, A.; Hihn, O.; Black, L.; Franz, T.; Negele, J.; Merten, C.; Marks, A.; Schraven, B.; Boettcher, M.; Sandmann, S.; Varghese, J.; Tueting, T.; Mougiakakos, D.; Schreiber, J.; Geffers, R.; Mueller, A. J.; Reinhold, D.; Fachet, M.; Stegemann Koniszewski, S.; Dudeck, A.; Weigelin, B.; Kahlfuss, S.

doi:10.1101/2025.09.17.676489

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bioRxiv · 10.1101/2025.09.17.676489

CD36 is a metabolic checkpoint for Th2 cell tissue residency during allergic airway inflammation

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Abstract

The prevalence of allergic diseases, including asthma, continues to rise in industrialized societies, yet the mechanisms sustaining pathogenic T helper 2 (Th2) responses remain incompletely understood. Here, we show that patients with allergic asthma exhibit elevated lipophilic volatile organic compounds in exhaled air and altered fatty acid-metabolism gene expression in sputum-derived Th2 cells. Using a mouse model of house dust mite-induced allergic airway inflammation, we find that the lipid transporter CD36 is dispensable for T follicular helper and germinal center B cell responses but is critical for maintaining lung-resident memory Th2 cells. CD36 regulates GATA3 and PPAR{gamma} expression in lung-resident memory Th2 cells and their interaction with type-2 conventional dendritic cells during airway inflammation. In human T cells, pharmacological inhibition of CD36 does not impair initial activation but blocks terminal Th2 differentiation. These findings identify CD36 as a metabolic checkpoint that sustains Th2 effector function and tissue residency, and establish lipid metabolism as a yet unrecognized therapeutic target in allergic asthma. SummaryAllergic asthma is marked by rising prevalence yet the drivers of persistent T helper 2 (Th2) immunity remain unclear. We show that asthma patients exhibit altered fatty acid-metabolism signatures in sputum Th2 cells and elevated lipophilic volatile organic compounds in exhaled air. In a mouse model of house dust mite-induced airway inflammation, the lipid transporter CD36 was dispensable for germinal center responses but essential for lung-resident memory Th2 cells, controlling GATA3 and PPAR{gamma} expression and promoting cDC2 interactions. Pharmacological inhibition of CD36 in human T cells preserved activation but blocked terminal Th2 differentiation. These findings identify CD36 as a metabolic checkpoint that sustains Th2 effector function and tissue residency, and nominate it as a therapeutic target in allergic asthma. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/676489v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@117da6eorg.highwire.dtl.DTLVardef@105934corg.highwire.dtl.DTLVardef@109903corg.highwire.dtl.DTLVardef@dc9345_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Krone, A., Schreiber, S., Jantz Naeem, N., Sammt, A., Dudeck, J., Katsoulis Dimitriou, K., Goihl, A., Hihn, O., Black, L., Franz, T., Negele, J., Merten, C., Marks, A., Schraven, B., Boettcher, M., Sandmann, S., Varghese, J., Tueting, T., Mougiakakos, D., Schreiber, J., Geffers, R., Mueller, A. J., Reinhold, D., Fachet, M., Stegemann Koniszewski, S., Dudeck, A., Weigelin, B., Kahlfuss, S.. 2025-09-20. CD36 is a metabolic checkpoint for Th2 cell tissue residency during allergic airway inflammation. https://doi.org/10.1101/2025.09.17.676489

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