Pirillo et al. showed that fluorescent antigen (Ag) encoded by influenza A virus, delivered intranasally, was carried by migratory cDCs (mDCs) from the infection site in mouse lung to dLN. Lung DCs, mDCs in dLN, and LN-resident DCs (rDCs) were activated upon viral Ag loading, and all shared the same activation phenotype, despite the rDCs’ distal location. CD4+ T cell depletion and IFNAR blockade did not prevent rDC activation. Viral Ag and dsRNA colocalized in intracellular vesicles of rDCs, and activation required MyD88. In a s.c. metastatic melanoma mouse model, intratumoral poly(I:C) co-transferred with tumor-derived Ag and boosted rDC activation.
Contributed by Paula Hochman
ABSTRACT: T cell responses against infections and cancer are directed by conventional dendritic cells (cDCs) in lymph nodes distant from the site of challenge. Migratory cDCs, which travel from the tissue to the lymph node, not only drive initial T cell activation but also transfer antigen to lymph node-resident cDCs. These resident cells have essential roles defining the character of the resulting T cell response; however, it is unknown how they can appropriately process and present antigens to suitably direct responses given their spatial separation. Here, using a novel strain of influenza A and a modified melanoma model, we show that tissue and lymph node cDC activation is harmonized and that this is driven by cotransfer of contextual cues. In the tumor, incomplete cDC activation in the tumor microenvironment is mirrored by lymph node-resident cDCs, whereas during influenza infection, pathogen-associated molecular patterns cotransferred with antigen drive TLR signaling in resident cDCs and their subsequent robust activation. This cotransfer mechanism explains how individual antigens can be handled distinctly by resident cDCs and how signals driving poor tumoral cDC activation further impact the lymph node. Our findings clarify how tissue context dictates antigenic and, consequently, T cell fate in the lymph node.
Author Info: (1) CRUK Beatson Institute, Glasgow, Great Britain. (2) CRUK Beatson Institute, Glasgow, Great Britain. (3) MRC-University of Glasgow Centre for Virus Research, Glasgow, Great Brit
Author Info: (1) CRUK Beatson Institute, Glasgow, Great Britain. (2) CRUK Beatson Institute, Glasgow, Great Britain. (3) MRC-University of Glasgow Centre for Virus Research, Glasgow, Great Britain. (4) CRUK Beatson Institute, Glasgow, Great Britain. (5) MRC-University of Glasgow Centre for Virus Research, Glasgow, Great Britain. Jinan Center for Disease Control and Prevention, Jinan, Shandong 250021, China. (6) MRC-University of Glasgow Centre for Virus Research, Glasgow, Great Britain. (7) MRC-University of Glasgow Centre for Virus Research, Glasgow, Great Britain. (8) School of Infection and Immunity, University of Glasgow, Glasgow, Great Britain. (9) CRUK Beatson Institute, Glasgow, Great Britain. (10) School of Cancer Sciences, University of Glasgow, Glasgow, Great Britain. (11) CRUK Beatson Institute, Glasgow, Great Britain. (12) MRC-University of Glasgow Centre for Virus Research, Glasgow, Great Britain. (13) School of Infection and Immunity, University of Glasgow, Glasgow, Great Britain. (14) MRC-University of Glasgow Centre for Virus Research, Glasgow, Great Britain. School of Infection and Immunity, University of Glasgow, Glasgow, Great Britain. (15) CRUK Beatson Institute, Glasgow, Great Britain. School of Cancer Sciences, University of Glasgow, Glasgow, Great Britain.
