TLR7 triggering with polyU promotes cross-presentation in CD8alpha+ cDCs by enhancing antigen preservation and MHC I-Ag permanence on DC surface

MARÍA INÉS CRESPO; ESTEFANÍA ZACCA; NICOLAS NUÑEZ; ROMINA P. RANOCCHIA; MARIANA MACCIONI; BELKYS A. MALETTO; MARÍA C PISTORESI- PALENCIA.; GABRIEL MORÓN

JOURNAL OF IMMUNOLOGY

AMER ASSOC IMMUNOLOGISTS

Lugar: Bethesda; Año: 2013 vol. 190 p. 948 - 960

0022-1767

Single stranded RNA (ssRNA) can interact with DCs through binding to Toll-like receptor (TLR) 7, inducing secretion of pro-inflammatory cytokines and type I IFN. Triggering TLR7 enhances cross-priming of CD8+ T cells, which requires cross-presentation of exogenous antigen (Ag) to dendritic cells (DCs). However, how TLR triggering can affect Ag cross-presentation is still not clear. Using ovalbumin (OVA) as an antigen model, we observed that stimulation of TLR7 in DCs by polyuridylic acid (polyU), a synthetic ssRNA analog, generates a strong specific cytotoxic response in C57BL/6 mice. PolyU stimulate CD8a+ DCs to cross-prime naïve CD8+ T cells in a type I IFN?dependent fashion. This enhanced cross-priming is accompanied by a higher density of OVA256-264-H2Kb complexes on CD8a+ DCs treated with polyU, as well as by up-regulation of co-stimulatory molecules and increased secretion of pro-inflammatory cytokines by DCs. Cross-priming of CD8+ T cells by DCs treated with polyU requires proteasome and Ag translocation to cytosol through Sec61 channel in DCs. The observed enhancement in OVA cross-presentation with polyU in DCs could be mediated by a limited Ag degradation in endophagosomal compartments and a higher permanence of OVA peptide-MHC I complexes on DCs. These observations clearly reveal that key steps of Ag processing for cross-presentation can be modulated by TLR ligands, opening new avenues for understanding their mechanisms as adjuvants of the immune response.