CD4+ CD25+ Foxp3- T-regulatory cells produce both gamma interferon and interleukin-10 during acute severe murine spotted fever rickettsiosis.
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 10(5) 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-gamma) and a higher level of IL-10, but not of IL-4 or transforming growth factor beta, 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-gamma 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-gamma-producing Th1 cells in the spleen, and increased the serum levels of IFN-gamma. 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.
Fang
Rong
R
Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555-0609, USA.
Ismail
Nahed
N
Shelite
Thomas
T
Walker
David H
DH
D000208:Acute Disease; D000818:Animals; D001907:Boutonneuse Fever / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000032:analysis; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D051379:Mice; D008809:Mice, Inbred C3H; D020114:Rickettsia conorii / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016753:Interleukin-10; D007371:Interferon-gamma