Clec7a-mediated regulation of Killer-like Lectin Receptor expression controls T cell immunity

Dambuza, I. M.; Salazar, F.; Sey, E. A.; Kastora, S. L.; Rodrigues, C.; Phillips-Brookes, A.; Harvey, J.; Drummond, R. A.; Rush, J.; Yuecel, R.; Saijo, S.; Willment, J. A.; Kaplan, D. H.; LeibundGut-Landmann, S.; Brown, G. D.

doi:10.64898/2025.12.04.692469

bioRxiv · 10.64898/2025.12.04.692469

Clec7a-mediated regulation of Killer-like Lectin Receptor expression controls T cell immunity

Dambuza, I. M.·Salazar, F.·Sey, E. A.·Kastora, S. L.·Rodrigues, C.·Phillips-Brookes, A.·Harvey, J.·Drummond, R. A.·Rush, J.·Yuecel, R.·Saijo, S.·Willment, J. A.·Kaplan, D. H.·LeibundGut-Landmann, S.·Brown, G. D.

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Abstract

Clec7a is a C-type lectin receptor (CLR) originally defined for its non-redundant role in anti-fungal immunity. Subsequent work has broadened this view, implicating Clec7a in host defense against diverse pathogens and in the pathogenesis of cancer, autoimmunity, neuroinflammation, and developmental disorders. How a single innate receptor orchestrates such wide-ranging outcomes remains unresolved. We previously demonstrated that dendritic cell (DC)-expressed Clec7a is required for protective anti-fungal immunity in the gastrointestinal tract through regulation of fungus-specific CD4 T cell responses. Here, we show that Clec7a controls the expression of multiple C-type lectins in DCs, including a cluster of killer lectin-like receptors (KLRs). Notably, we reveal that these KLRs directly regulate DC function and control CD4 T cell responses. These findings define a novel Clec7a-KLR axis that integrates innate and adaptive immunity, highlighting a regulatory pathway with broad relevance for immune homeostasis, inflammation, and host defense.

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Dambuza, I. M., Salazar, F., Sey, E. A., Kastora, S. L., Rodrigues, C., Phillips-Brookes, A., Harvey, J., Drummond, R. A., Rush, J., Yuecel, R., Saijo, S., Willment, J. A., Kaplan, D. H., LeibundGut-Landmann, S., Brown, G. D.. 2025-12-09. Clec7a-mediated regulation of Killer-like Lectin Receptor expression controls T cell immunity. https://doi.org/10.64898/2025.12.04.692469

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