Efficient major histocompatibility complex class II-restricted presentation of measles virus relies on hemagglutinin-mediated targeting to its cellular receptor human CD46 expressed by murine B cells.

Abstract

SummaryMeasles virus after binding to its cell surface human CD46 receptor fuses with the plasma membrane. This fusion results in envelope hemagglutinin (H) and fusion glycoprotein (F) incorporated into the plasma membrane and injection of the nucleocapsid made of nucleoprotein (NP) into the cytosol. The influence of targeting measles virus (MV) to CD46 in the processing and presentation of MV H and NP to antigen specific MHC class II bE d-and bAd-restricted T cell hybridomas was explored using murine M12-CD46 B cell transfectants. Parent M12 cells, which lack any MV receptor, were unable to present any of these two viral proteins when incubated with MV particles. Incubating M12.CD46 cells with 200 ng and 10/zg of MV could strongly stimulate H-specific and NP-specific T cells, respectively. Neosynthesis of MV proteins was not necessary since the efficiency of antigen presentation was similar when using ultraviolet-inactivated MV. Similar enhancing effects (more than 1,000-fold) on antigen presentation were also observed when using purified native H soluble or incorporated into liposomes whereas denaturating H glycoprotein resulted in a poor efficiency in T cell stimulation, M12.CD46 being no more potent than the parental M12 counterpart. MV H and NP presentation efficiency did not depend on MV fusion with plasma membrane as revealed by the lack of effect of specific fusion inhibitors. Both MV H and NP presentations were sensitive to chloroquine inhibition indicating that antigens from CD46-mediated captured MV were likely processed in the endosome/lysosome compartment. Altogether these data indicate that (a) MV targeting via CD46 has a strong effect on the efficiency of antigen presentation by MHC class II, (b) the effect is mediated by the binding of H to CD46, and (c) though MV does fuse with plasma membrane, endocytosis, and processing of virus particles are also occurring. Since, in humans, CD46 is expressed in almost every tissue including professional antigen-presenting cells, such a targeting is likely to play a crucial role in the CD4 + T cell-mediated primary immune response against the pathogen in vivo.

B Cell Receptors and Complement Receptors Target the Antigen to Distinct Intracellular Compartments

“…Like other GPI receptors, it may be internalized into caveolae vesicles devoid of TfR. MCP is a transmembrane receptor that can induce efficient Ag presentation by MHC-II (59,60), indicating that this receptor gains access to some peptideloading compartments, but its intracellular traffic has not been characterized. Furthermore, DAF and MCP are strongly expressed on B lymphocytes.…”

Measles virus receptor properties are shared by several CD46 isoforms differing in extracellular regions and cytoplasmic tails

“…Accordingly, a monoclonal antibody (MAb), MCI20.6, later identified as recognizing CD46, can inhibit MV binding, MV-induced cell-cell fusion and MV infection of human cells (Naniche et al, 1992). We have shown recently that MV envelope glycoprotein HA binds to CD46 (Gerlier et al, 1994). In addition, as observed for many other virus receptors, MV infection of human cells leads to a specific down-regulation of cell surface expression of CD46 (Naniche et al, 1993b).…”

γδ T cells present antigen to CD4+ αβ T cells

“…Alternatively, antigen can enter cells either via a process of fluid phase uptake [12] or by molecules not dedicated to this activity [13]. Such a mode of entry is used for the processing of some viral antigens [14]. To recycle internalized antigens to the cell surface as peptide-MHC class II complexes, APC require the provision of endosomal pathways [15,16].…”