IRF4 Transcription Factor-Dependent CD11b ⁺ Dendritic Cells in Human and Mouse Control Mucosal IL-17 Cytokine Responses

Summary

Mouse and human dendritic cells (DCs) are composed of functionally specialized subsets, but precise interspecies correlation is currently incomplete. Here, we showed that murine lung and gut lamina propria CD11b ⁺ DC populations were comprised of two subsets: FLT3- and IRF4-dependent CD24 ⁺CD64 ⁻ DCs and contaminating CSF-1R-dependent CD24 ⁻CD64 ⁺ macrophages. Functionally, loss of CD24 ⁺CD11b ⁺ DCs abrogated CD4 ⁺ T cell-mediated interleukin-17 (IL-17) production in steady state and after Aspergillus fumigatus challenge. Human CD1c ⁺ DCs, the equivalent of murine CD24 ⁺CD11b ⁺ DCs, also expressed IRF4, secreted IL-23, and promoted T helper 17 cell responses. Our data revealed heterogeneity in the mouse CD11b ⁺ DC compartment and identifed mucosal tissues IRF4-expressing DCs specialized in instructing IL-17 responses in both mouse and human. The demonstration of mouse and human DC subsets specialized in driving IL-17 responses highlights the conservation of key immune functions across species and will facilitate the translation of mouse in vivo findings to advance DC-based clinical therapies.

Highlights

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  Mucosal CD11b ⁺ DCs consist of CD24 ⁺CD64 ⁻ DCs and CD24 ⁻CD64 ⁺ macrophages

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  Mucosal CD24 ⁺CD11b ⁺ DCs are IRF4-dependent

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  IRF4-dependent CD24 ⁺CD11b ⁺ DCs secrete IL-23α and control mucosal IL-17 responses

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  Human CD1c ⁺CD11b ⁺ DCs are functional homologs of murine CD24 ⁺CD11b ⁺ DCs