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

Abstract

SummaryMouse 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.

Immunotherapeutic Effects of Dendritic Cells Pulsed with a Coden-optimized HPV 16 E6 and E7 Fusion Gene in Vivo and in Vitro

“…Dendritic cells (DCs) are the most potent professional antigen processing cells of the immune system with their essential roles in induction and control of T-cell immunity (Kozłowska et al, 2013). Genetic modification of DCs with genes encoding immunoregulatory molecules provides a potential approach for Ag-specific regulation of T cellmediated immunity by selectively targeting antigenspecific T cells (Meixlsperger et al, 2013;Schlitzer et al, 2013). Cellular vaccines based on DCs pulsed with antigens have previously been studied for HPV-associated tumour growth protection or immunotherapy (Ramanathan et al, 2014).…”

CD11b+DCs rediscovered: implications for vaccination

“…Ontogenetically, NLT CD11b + DCs (expressing MHC-II, CD11c and CD11b) were thought to arise from both bone marrow (BM) DC-specific progenitors and monocytes, with partial dependence on both FLT3 and the macrophage/monocyte lineage growth factor receptor, CSF-1R, for their differentiation [7]. However, reanalysis of the CD11b + DC compartment using CD24 (DC marker) and CD64/MerTK (macrophage markers) improved discrimination of DCs and macrophages, revealing the true bona fide DC nature of the CD24 + CD11b + population, which is purely dependent on FLT3 for its differentiation [8,9]. CD11b + DCs were also found to depend on various other transcription factors (TFs) such as NOTCH2, RELB and IRF4 [6,[8][9][10].…”

“…However, reanalysis of the CD11b + DC compartment using CD24 (DC marker) and CD64/MerTK (macrophage markers) improved discrimination of DCs and macrophages, revealing the true bona fide DC nature of the CD24 + CD11b + population, which is purely dependent on FLT3 for its differentiation [8,9]. CD11b + DCs were also found to depend on various other transcription factors (TFs) such as NOTCH2, RELB and IRF4 [6,[8][9][10]. These recent developments illustrate the importance of analyses of growth factor and TF requirements of DC subsets in advancing our understanding of their inter-relationships.…”

“…Aside from this, recent studies have indicated that lung CD11b + DCs are potent stimulators of Th17 immunity through release of IL-23 in both steady state and upon Aspergillus fumigatus infection [8]. Similarly, intestinal CD11b + CD103 + DCs, unique to the intestine, control the induction of Th17 immunity [8,9].…”

The thymic medulla: who needs it?

“…IRF4-dependent CD103 À CD11b þ DCs were identified in the lung and gut, where they played a particular role in mucosal immunity by induction of Th17 cells after fungal infection. 9 CD1c þ DCs, which include circulating and inflammatory populations represent equivalent populations in human tissues. Given that commensal or pathogenic microbes produce not only endotoxin but also xenobiotic ligands, these RelB-dependent DCs are ideally located to respond under inflammatory settings and could potentially be the DCs in which AhR signalling is acting.…”