CD40 ligand enhances dengue viral infection of dendritic cells: a possible mechanism for T cell-mediated immunopathology.
We have previously shown that dengue virus (DV) productively infects immature human dendritic cells (DCs) through binding to cell surface DC-specific ICAM-3-grabbing nonintegrin molecules. Infected DCs are apoptotic, refractory to TNF-alpha stimulation, inhibited from undergoing maturation, and unable to stimulate T cells. In this study, we show that maturation of infected DCs could be restored by a strong stimulus, CD40L. Addition of CD40L significantly reduced apoptosis of DCs, promoted IL-12 production, and greatly elevated the IFN-gamma response of T cells, but yet did not restore T cell proliferation in MLR. Increased viral infection of DCs was also observed; however, increased infection did not appear to be mediated by DC-specific ICAM-3-grabbing nonintegrin, but rather was regulated by decreased production of IFN-alpha and decreased apoptotic death of infected DCs. Because CD40L is highly expressed on activated memory (but not naive) T cells, the observation that CD40L signaling results in enhanced DV infection of DC suggests a possible T cell-dependent mechanism for the immune-mediated enhancement of disease severity associated with some secondary dengue infections.
Sun
Peifang
P
Naval Medical Research Center, Silver Spring, MD 20910, USA.
Celluzzi
Christina M
CM
Marovich
Mary
M
Subramanian
Hemavathy
H
Eller
Michael
M
Widjaja
Susana
S
Palmer
Dupeh
D
Porter
Kevin
K
Sun
Wellington
W
Burgess
Timothy
T
D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D023201:CD40 Ligand / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D003715:Dengue / Q000276:immunology; D003716:Dengue Virus / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D015854:Up-Regulation
D015703:Antigens, CD; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D016207:Cytokines; C483616:ICAM3 protein, human; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma