Shared pathway of WDFY4-dependent cross-presentation of immune complexes by cDC1 and cDC2

Area of Science:

• Immunology
• Cell Biology
• Dendritic Cell Biology

Background:

• Cross-presentation of exogenous antigens by type 1 conventional dendritic cells (cDC1s) is crucial for priming CD8+ T cells against tumors and viruses.
• The in vivo physiological roles of antigen cross-presentation by other dendritic cell subsets, such as cDC2s and monocyte-derived DCs, remain less understood.

Purpose of the Study:

• To investigate the in vivo roles of different dendritic cell subsets in presenting cell-associated and immune complex antigens to CD4+ and CD8+ T cells.
• To elucidate the mechanisms and identify key molecules involved in antigen cross-presentation by various dendritic cell subsets.

Main Methods:

• Utilized genetic mouse models to assess the function of specific dendritic cell subsets.
• Evaluated the cross-presentation of both cell-associated antigens and immune complex antigens.
• Analyzed T cell priming (CD4+ and CD8+) and functional outcomes like tumor rejection.

Main Results:

• cDC1s are essential and sufficient for priming both CD4+ and CD8+ T cells with cell-associated antigens.
• For immune complex antigens, both cDC1 and cDC2 subsets can perform cross-presentation to CD8+ T cells, while monocyte-derived DCs cannot.
• Depletion of cDC1s did not prevent CD8+ T cell priming and tumor rejection when using immune complex vaccination, indicating a compensatory role for cDC2s.
• WDFY4 was identified as a crucial molecule for cDC2-mediated cross-presentation of immune complexes, similar to its role in cDC1s.

Conclusions:

• Dendritic cell subset 2 (cDC2) possesses a significant, previously unrecognized capacity for cross-presenting immune complex antigens in vivo.
• A shared WDFY4-dependent cross-presentation pathway exists between cDC1 and cDC2 subsets, highlighting functional plasticity.
• These findings expand our understanding of T cell priming mechanisms and suggest potential therapeutic strategies involving different dendritic cell populations.