Systemic tumor necrosis factor generated during lethal Plasmodium infections impairs dendritic cell function.
Dendritic cells (DCs) initiate innate and adaptive immune responses including those against malaria. Although several studies have shown that DC function is normal during malaria, other studies have shown compromised function. To establish why these studies had different findings, we examined DCs from mice infected with two lethal species of parasite, Plasmodium berghei or P. vinckei, and compared them to DCs from nonlethal P. yoelii 17XNL or P. chabaudi infections. These studies found that DCs from only the lethal infections became uniformly mature 7 days after infection and were functionally impaired as they were unable to endocytose latex particles, secrete IL-12, or present OVA to transgenic OTII T cells. These changes coincided with a peak in levels of systemic TNF-alpha. Because TNF-alpha is known to mature DCs, we used TNF-KO mice to determine the role of this cytokine in the loss of DC function. In the TNF-KO mice, phenotype, Ag presentation, and IL-12 secretion by DCs were restored to normal following both lethal infections. This study shows that the systemic production of TNF-alpha contributes to poor DC function during lethal infections. These studies may explain, at least in part, immunosuppression that is associated with malaria.
Wykes
Michelle N
MN
The Molecular Immunology Laboratory, The Queensland Institute of Medical Research, The Bancroft Centre, Brisbane, Queensland, Australia.
Liu
Xue Q
XQ
Jiang
Suhua
S
Hirunpetcharat
Chakrit
C
Good
Michael F
MF
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000941:Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D004705:Endocytosis / Q000276:immunology; D005260:Female; D007108:Immune Tolerance / Q000235:genetics; D008288:Malaria / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010962:Plasmodium berghei / Q000276:immunology; D016788:Plasmodium chabaudi / Q000276:immunology; D010967:Plasmodium yoelii / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000097:blood* / Q000172:deficiency / Q000235:genetics