Exosome-mediated MHCII cross-presentation substantially enhanced by the receptor binding activity of influenza hemeagglutinin (130.10)

Abstract

Abstract T cell responses to viral infection often depend upon cross-presentation, a process in which antigen is transferred from an infected cell to a professional antigen presenting cell. This process has been extensively studied with respect to MHC class I-restricted activation of CD8+ T cells, with several mechanisms having been reported including transfer of peptide-loaded heat shock proteins, apoptotic bodies and exosomes. In contrast, little work has been done on MHCII-restricted cross-presentation. Using infectious influenza virus and its glycoproteins expressed in antigen presenting cells, we readily observed MHCII cross-presentation, but only for one of the three epitopes that we routinely study, the “S1” epitope of the hemagglutinin glycoprotein (HA). This selectivity was explained by subsequent experiments that identified the process to be exosome-mediated. While exosomes are naturally endocytosed at a basal level, blocking antibodies and neuraminidase treatment of acceptor APCs revealed that cross-presentation was substantially enhanced by the sialic acid binding activity of the HA that had been incorporated into exosomes produced by the donor cells. This mechanism could provide an explanation for the skewed CD4+ responses to influenza that have been reported and may be an important component of the immune response to other enveloped viruses.