Measles virus induces apoptosis in uninfected bystander T cells and leads to granzyme B and caspase activation in peripheral blood mononuclear cell cultures.
BACKGROUND
Measles causes lymphopenia and depresses cell-mediated immunity, but the mechanisms of immunosuppression and cell loss are poorly known.


METHODS
We have used an in vitro model of measles virus (MV)-infected peripheral blood mononuclear cells (PBMCs) and phytohaemagglutinin-stimulated PBMCs in order to assess MV-leucocyte interactions. Cell population undergoing apoptosis was measured by flow cytometry and Annexin-V-fluos staining. The expression of Fas, FasL, TNRF1, and Bcl-2 was analyzed by flow cytometry and Western blotting, and activation of caspase cascade was measured using a colourimetric caspase substrate set. The effects of caspase inhibitors were detected by flow cytometry.


RESULTS
Measles virus was able to infect monocytes, but interestingly induced apoptosis in uninfected T cells, indicating that induction of apoptosis in T cells is mediated by MV-infected adherent cells. Only 1% of T cells contained MV antigen day 3 p.i. Interestingly the percentage of early apoptotic T cells at the same time was 35%, showing that apoptosis was not the result of MV infection in T cells. Measles virus-induced Fas but not FasL or TNFR1 expression on PMBC, as well as activation of granzyme B and caspase cascade. Simultaneously, overexpression of Bcl-2 protein was detected. Caspase inhibitor decreased the amount of apoptotic T cells.


CONCLUSIONS
Measles virus-infected monocytes induce apoptosis in uninfected T cells, suggesting that infected monocytes probably interact via cell-surface molecules with uninfected T cells and induce apoptosis by indirect mechanisms. Apoptosis of the lymphocytes may contribute to the pathogenesis of MV-induced immunosuppression and cell loss.
Vuorinen
T
T
University of Turku, Turku, Finland. tytti.vyorinen@utu.fi
Peri
P
P
Vainionpää
R
R
D015703:Antigens, CD / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D015153:Blotting, Western; D020169:Caspases / Q000276:immunology*; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D005434:Flow Cytometry / Q000379:methods; D053804:Granzymes; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008459:Measles virus / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I; D012697:Serine Endopeptidases / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; D020169:Caspases