Measles Virus Infects Human Dendritic Cells and Blocks Their Allostimulatory Properties for CD4+ T Cells

Abstract

Measles causes a profound immune suppression which is responsible for the high morbidity and mortality induced by secondary infections. Dendritic cells (DC) are professional antigen-presenting cells required for initiation of primary immune responses. To determine whether infection of DC by measles virus (MV) may play a role in virus-induced suppression of cell-mediated immunity, we examined the ability of CD1a+ DC derived from cord blood CD34+ progenitors and Langerhans cells isolated from human epidermis to support MV replication. Here we show that both cultured CD1a+ DC and epidermal Langerhans cells can be infected in vitro by both vaccine and wild type strains of MV. DC infection with MV resulted within 24–48 h in cell–cell fusion, cell surface expression of hemagglutinin, and virus budding associated with production of infectious virus. MV infection of DC completely abrogated the ability of the cells to stimulate the proliferation of naive allogeneic CD4+ T cell as early as day 2 of mixed leukocyte reaction (MLR) (i.e., on day 4 of DC infection). Mannose receptor–mediated endocytosis and viability studies indicated that the loss of DC stimulatory function could not be attributed to the death or apoptosis of DC. This total loss of DC stimulatory function required viral replication in the DC since ultraviolet (UV)-inactivated MV or UV-treated supernatant from MV-infected DC did not alter the allostimulatory capacity of DC. As few as 10 MV- infected DC could block the stimulatory function of 104 uninfected DC. More importantly, MV-infected DC, in which production of infectious virus was blocked by UV treatment or paraformaldehyde fixation, actively suppressed allogeneic MLR upon transfer to uninfected DC–T-cultures. Thus, the mechanisms which contribute to the loss of the allostimulatory function of DC include both virus release and active suppression mediated by MV-infected DC, independent of virus production. These data suggest that carriage of MV by DC may facilitate virus spreading to secondary lymphoid organs and that MV replication in DC may play a central role in the general immune suppression observed during measles.

Poxvirus as a vector to transduce human dendritic cells for immunotherapy: abortive infection but reduced APC function

“…This is comparable with the resistance of mature DC to influenza virus infections, 30 but is in contrast to measles virus, which replicates in immature and even more efficiently in mature DC. 31,32 The cytokines IL-4 and GM-CSF added to immature and mature DC are not known to have antiviral effects. Possibly, the DC derived from blood monocytes as used here retained their non-permissive phenotype that has been described for VV infected blood monocytes/macrophages.…”

“…Interference with mature DC functions has also been described for measles virus. 31,32 However, in contrast to the measles virus, VV infection of DC is abortive. This excludes secondary VV infection of T cells as the cause of a reduced proliferative response in MLR.…”

Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response

“…Viral infection induces formation of DC syncytia, followed by the loss of the DC's capacity to stimulate naive CD4 1 T cells resulting in inhibition of CD4 1 T-cell proliferation [4][5][6] . MV-induced inhibition of T-cell functions was suggested to be mediated through either transmission of infectious virus to T cells, leading to a cell cycle block 8,9 and/or delivery of inhibitory signals via infected DCs [4][5][6] . In addition, MV binds DC-SIGN 10 , which could lead to the inhibition of type I IFN responses in DCs via blocking of RIG-I and MDA5 dephosphorylation 11 .…”

“…Different subsets of DCs, including skin Langerhans cells 4 , peripheral blood DCs 5 , CD34 1 -derived DCs 4 , and monocyte-derived DCs 6 are permissive to MV infection and seem to have subset-specific interferon-inducing systems 7 . Viral infection induces formation of DC syncytia, followed by the loss of the DC's capacity to stimulate naive CD4 1 T cells resulting in inhibition of CD4 1 T-cell proliferation [4][5][6] .…”

“…Different subsets of DCs, including skin Langerhans cells 4 , peripheral blood DCs 5 , CD34 1 -derived DCs 4 , and monocyte-derived DCs 6 are permissive to MV infection and seem to have subset-specific interferon-inducing systems 7 . Viral infection induces formation of DC syncytia, followed by the loss of the DC's capacity to stimulate naive CD4 1 T cells resulting in inhibition of CD4 1 T-cell proliferation [4][5][6] . MV-induced inhibition of T-cell functions was suggested to be mediated through either transmission of infectious virus to T cells, leading to a cell cycle block 8,9 and/or delivery of inhibitory signals via infected DCs [4][5][6] .…”