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Infection and Immunity, April 2008, p. 1434-1444, Vol. 76, No. 4
0019-9567/08/$08.00+0     doi:10.1128/IAI.01242-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Regulatory Roles of CD1d-Restricted NKT Cells in the Induction of Toxic Shock-Like Syndrome in an Animal Model of Fatal Ehrlichiosis{triangledown}

H. L. Stevenson, E. C. Crossley, N. Thirumalapura, D. H. Walker, and N. Ismail*

Department of Pathology and Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, Texas 77555-0609

Received 10 September 2007/ Returned for modification 22 October 2007/ Accepted 15 January 2008

CD1d-restricted NKT cells are key players in host defense against various microbial infections. Using a murine model of fatal ehrlichiosis, we investigated the role of CD1d-restricted NKT cells in induction of toxic shock-like syndrome caused by gram-negative, lipopolysaccharide-lacking, monocytotropic Ehrlichia. Our previous studies showed that intraperitoneal infection of wild-type (WT) mice with virulent Ehrlichia (Ixodes ovatus Ehrlichia [IOE]) results in CD8+ T-cell-mediated fatal toxic shock-like syndrome marked by apoptosis of CD4+ T cells, a weak CD4+ Th1 response, overproduction of tumor necrosis factor alpha and interleukin-10, and severe liver injury. Although CD1d–/– mice succumbed to high-dose IOE infection similar to WT mice, they did not develop signs of toxic shock, as shown by elevated bacterial burdens, low serum levels of tumor necrosis factor, normal serum levels of liver enzymes, and the presence of few apoptotic hepatic cells. An absence of NKT cells restored the percentages and absolute numbers of CD4+ and CD8+ T cells and CD11b+ cells in the spleen compared to WT mice and was also associated with decreased expression of Fas on splenic CD4+ lymphocytes and granzyme B in hepatic CD8+ lymphocytes. Furthermore, our data show that NKT cells promote apoptosis of macrophages and up-regulation of the costimulatory molecule CD40 on antigen-presenting cells, including dendritic cells, B cells, and macrophages, which may contribute to the induction of pathogenic T-cell responses. In conclusion, our data suggest that NKT cells mediate Ehrlichia-induced T-cell-mediated toxic shock-like syndrome, most likely via cognate and noncognate interactions with antigen-presenting cells.

* Corresponding author. Mailing address: Department of Pathology and Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX 77555-0609. Phone: (409) 772-3111. Fax: (409) 772-5683. E-mail: naismail{at}utmb.edu

{triangledown} Published ahead of print on 22 January 2008.

Editor: R. P. Morrison

Infection and Immunity, April 2008, p. 1434-1444, Vol. 76, No. 4
0019-9567/08/$08.00+0     doi:10.1128/IAI.01242-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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