CCR2(+)CD103(-) intestinal dendritic cells develop from DC-committed precursors and induce interleukin-17 production...

Area of Science:

• Immunology
• Gastroenterology
• Cell Biology

Background:

• The precise identification and classification of mononuclear phagocytes (MPs), specifically intestinal macrophages (mφs) and dendritic cells (DCs), remain a subject of ongoing scientific debate.
• While CD103(+) MPs are generally accepted as DCs, the identity and origins of CD103(-) MPs are less clear, necessitating further investigation into their distinct roles.

Purpose of the Study:

• To differentiate and characterize the heterogeneous CD103(-)CD11b(+) mononuclear phagocyte population in the intestine.
• To identify specific subsets of dendritic cells (DCs) within the CD103(-)CD11b(+) population and elucidate their functional roles in immune responses.

Main Methods:

• Utilizing flow cytometry, gene profiling, and kinetic analysis to distinguish between intestinal macrophages and dendritic cells.
• Investigating the role of the chemokine receptor CCR2 in the development and function of intestinal CD103(-)CD11b(+) DCs.
• Assessing the capacity of identified DC subsets to prime T cells for specific cytokine production, including IL-17a.

Main Results:

• Intestinal CD103(-)CD11b(+) MPs were successfully separated into distinct DC and mφ populations based on phenotypic, genetic, and kinetic markers.
• A subset of classical DCs, identified as CD64(-)CD103(-)CD11b(+), were found to be Flt3 ligand-dependent and not derived from Ly6C(hi) monocytes.
• A significant proportion of these CD103(-)CD11b(+) DCs express CCR2, and their absence in CCR2-deficient mice highlights the receptor's importance. These CCR2(+)CD103(-) DCs are present in both murine and human intestines, constitutively express IL-12/IL-23p40, and drive IL-17a production by T cells.
• These findings reveal a novel population of CCR2(+) DCs involved in initiating mucosal T helper type 17 (Th17) responses.

Conclusions:

• The intestinal CD103(-)CD11b(+) mononuclear phagocyte pool is heterogeneous, comprising distinct populations of dendritic cells and macrophages.
• A novel subset of CCR2(+)CD103(-) dendritic cells has been identified in the murine and human intestine, playing a critical role in priming mucosal Th17 responses.
• These findings contribute to a better understanding of intestinal immune cell heterogeneity and the specific functions of dendritic cells in mucosal immunity.