title: Relative importance of T-cell subsets in monocytotropic ehrlichiosis: a novel effector mechanism involved in Ehrlichia-induced immunopathology in murine ehrlichiosis.
abstract: Infection with gram-negative monocytotropic Ehrlichia strains results in a fatal toxic shock-like syndrome characterized by a decreased number of Ehrlichia-specific CD4(+) Th1 cells, the expansion of tumor necrosis factor alpha (TNF-alpha)-producing CD8(+) T cells, and the systemic overproduction of interleukin-10 (IL-10) and TNF-alpha. Here, we investigated the role of CD4(+) and CD8(+) T cells in immunity to Ehrlichia and the pathogenesis of fatal ehrlichiosis caused by infection with low- and high-dose (10(3) and 10(5) bacterial genomes/mouse, respectively) ehrlichial inocula. The CD4(+) T-cell-deficient mice showed exacerbated susceptibility to a lethal high- or low-dose infection and harbored higher bacterial numbers than did wild-type (WT) mice. Interestingly, the CD8(+) T-cell-deficient mice were resistant to a low dose but succumbed to a high dose of Ehrlichia. The absence of CD8(+) T cells abrogated TNF-alpha and IL-10 production, reduced tissue injury and bacterial burden, restored splenic CD4(+) T-cell numbers, and increased the frequency of Ehrlichia-specific CD4(+) Th1 cells in comparison to infected WT mice. Although fatal disease is perforin independent, our data suggested that perforin played a critical role in controlling bacterial burden and mediating liver injury. Similar to WT mice, mortality of infected perforin-deficient mice was associated with CD4(+) T-cell apoptosis and a high serum concentration of IL-10. Depletion of IL-10 restored the number of CD4(+) and CD8(+) T cells in infected WT mice. Our data demonstrate a novel mechanism of immunopathology in which CD8(+) T cells mediate Ehrlichia-induced toxic shock, which is associated with IL-10 overproduction and CD4(+) T-cell apoptosis.
authors.affiliation: Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, 301 University Blvd., Galveston, TX 77555-0609, USA. naismail@utmb.edu
authors.forename: Nahed
authors.initials: N
authors.lastname: Ismail
authors.forename: Emily C
authors.initials: EC
authors.lastname: Crossley
authors.forename: Heather L
authors.initials: HL
authors.lastname: Stevenson
authors.forename: David H
authors.initials: DH
authors.lastname: Walker
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D018469:Ehrlichia chaffeensis / Q000276:immunology; D016873:Ehrlichiosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics
chemical_list: D001613:beta 2-Microglobulin