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Infection and Immunity, September 2009, p. 3838-3849, Vol. 77, No. 9
0019-9567/09/$08.00+0     doi:10.1128/IAI.00349-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

CD4⁺ CD25⁺ Foxp3^– T-Regulatory Cells Produce both Gamma Interferon and Interleukin-10 during Acute Severe Murine Spotted Fever Rickettsiosis ^,

Rong Fang,¹ Nahed Ismail,^1,3 Thomas Shelite,¹ and David H. Walker^1,2*

Department of Pathology, University of Texas Medical Branch, Galveston, Texas,¹ Center for Biodefense and Emerging Infectious Diseases, 301 University Blvd., Galveston, Texas 77555-0609,² Department of Pathology, Meharry Medical College, 1005 Dr. D. B. Todd Jr. Blvd., Nashville, Tennessee 37208³

Received 26 March 2009/ Returned for modification 25 April 2009/ Accepted 18 June 2009

Spotted fever group rickettsiae cause life-threatening human infections worldwide. Until now, the immune regulatory mechanisms involved in fatal rickettsial infection have been unknown. C3H/HeN mice infected with 3 x 10⁵ PFU of Rickettsia conorii developed an acute progressive disease, and all mice succumbed to this infection. A sublethal infection induced protective immunity, and mice survived. Compared to splenic T cells from sublethally infected mice, splenic T cells from lethally infected mice produced significantly lower levels of interleukin-2 (IL-2) and gamma interferon (IFN-) and a higher level of IL-10, but not of IL-4 or transforming growth factor β, and there was markedly suppressed CD4⁺ T-cell proliferation in response to antigen-specific stimulation with R. conorii. Furthermore, lethal infection induced significant expansion of CD4⁺ CD25⁺ Foxp3^– T cells in infected organs compared to the levels in naïve and sublethally infected mice. In a lethal infection, splenic CD4⁺ CD25⁺ Foxp3^– T cells, which were CTLA-4^high T-bet⁺ and secreted both IFN- and IL-10, suppressed the proliferation of and IL-2 production by splenic CD4⁺ CD25^– Foxp3^– T cells in vitro. Interestingly, depletion of CD25⁺ T cells in vivo did not change the disease progression, but it increased the bacterial load in the lung and liver, significantly reduced the number of IFN--producing Th1 cells in the spleen, and increased the serum levels of IFN-. These results suggested that CD4⁺ CD25⁺ T cells generated in acute murine spotted fever rickettsiosis are Th1-cell-related adaptive T-regulatory cells, which substantially contribute to suppressing the systemic immune response, possibly by a mechanism involving IL-10 and/or cytotoxic T-lymphocyte antigen 4.

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* Corresponding author. Mailing address: Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, 301 University Blvd., Galveston, TX 77555-0609. Phone: (409) 772-3989. Fax: (409) 772-1850. E-mail: dwalker{at}utmb.edu

Published ahead of print on 29 June 2009.

Supplemental material for this article may be found at http://iai.asm.org/.

Editor: W. A. Petri, Jr.

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Infection and Immunity, September 2009, p. 3838-3849, Vol. 77, No. 9
0019-9567/09/$08.00+0     doi:10.1128/IAI.00349-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.