Recent progress in type 1 classical dendritic cell cross-presentation - cytosolic, vacuolar, or both?

Type 1 classical dendritic cells (cDC1s) have emerged as the major antigen-presenting cell performing cross-presentation (XP) in vivo, but the antigen-processing pathway in this cell remains obscure. Two competing models for in vivo XP of cell-associated antigens by cDC1 include a vacuolar pathway and cytosolic pathway. A vacuolar pathway relies on directing antigens captured in vesicles toward a class I major histocompatibility complex loading compartment independently of cytosolic entry. Alternate proposals invoke phagosomal rupture, either constitutive or triggered by spleen tyrosine kinase (SYK) signaling in response to C-type lectin domain family 9 member A (CLEC9A) engagement, that releases antigens into the cytosol for proteasomal degradation. The Beige and Chediak-Higashi (BEACH) protein WD repeat- and FYVE domain-containing protein 4 (WDFY4) is strictly required for XP of cell-associated antigens in vivo. However, the cellular mechanism for WDFY4 activity remains unknown and its requirement in XP in vivo is currently indifferent regarding the vacuolar versus cytosolic pathways. Here, we review the current status of these models and discuss the need for future investigation.