Activation of Invariant NKT Cells Exacerbates Experimental Visceral Leishmaniasis

PLoS Pathogens

Mark J. Smyth¹  Dale I. Godfrey²  Daniel G. Pellicci²  Ashraful Haque³  Geoff R. Hill³  Fiona H. Amante³  Yonghong Zhou³  Amanda C. Stanley³  Louise M. Randall³  Christian R. Engwerda³ 

[1] Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia;Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia;Immunology and Infection Laboratory, Queensland Institute of Medical Research, Herston, Queensland, Australia

关键词: Parasitic diseases;    Leishmania donovani;    T cells;    Cytokines;    NK cells;    Cytotoxic T cells;    Infectious disease control;    Cell physiology;   

DOI  :  10.1371/journal.ppat.1000028

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

We report that natural killer T (NKT) cells play only a minor physiological role in protection from Leishmania donovani infection in C57BL/6 mice. Furthermore, attempts at therapeutic activation of invariant NKT (iNKT) cells with α-galactosylceramide (α-GalCer) during L. donovani infection exacerbated, rather than ameliorated, experimental visceral leishmaniasis. The inability of α-GalCer to promote anti-parasitic immunity did not result from inefficient antigen presentation caused by infection because α-GalCer–loaded bone marrow–derived dendritic cells were also unable to improve disease resolution. The immune-dampening affect of α-GalCer correlated with a bias towards increased IL-4 production by iNKT cells following α-GalCer stimulation in infected mice compared to naïve controls. However, studies in IL-4–deficient mice, and IL-4 neutralisation in cytokine-sufficient mice revealed that α-GalCer–induced IL-4 production during infection had only a minor role in impaired parasite control. Analysis of liver cell composition following α-GalCer stimulation during an established L. donovani infection revealed important differences, predominantly a decrease in IFNγ+ CD8+ T cells, compared with control-treated mice. Our data clearly illustrate the double-edged sword of NKT cell–based therapy, showing that in some circumstances, such as when sub-clinical or chronic infections exist, iNKT cell activation can have adverse outcomes.

【 授权许可】

CC BY