title: Active evasion of CTL mediated killing and low quality responding CD8+ T cells contribute to persistence of brucellosis.
abstract: Brucellosis is a common zoonotic disease that remains endemic in many parts of the world. Dissecting the host immune response during this disease provides insight as to why brucellosis is often difficult to resolve. We used a Brucella epitope specific in vivo killing assay to investigate the ability of CD8+ T cells to kill targets treated with purified pathogenic protein. Importantly, we found the pathogenic protein TcpB to be a novel effector of adaptive immune evasion by inhibiting CD8+ T cell killing of Brucella epitope specific target cells in mice. Further, BALB/c mice show active Brucella melitensis infection beyond one year, many with previously unreported focal infection of the urogenital area. A fraction of CD8+ T cells show a CD8+ Tmem phenotype of LFA-1hi, CD127hi, KLRG-1lo during the course of chronic brucellosis, while the CD8+ T cell pool as a whole had a very weak polyfunctional cytokine response with diminished co-expression of IFN-γ with TNFα and/or IL-2, a hallmark of exhaustion. When investigating the expression of these 3 cytokines individually, we observed significant IFN-γ expression at 90 and 180 days post-infection. TNFα expression did not significantly exceed or fall below background levels at any time. IL-2 expression did not significantly exceeded background, but, interestingly, did fall significantly below that of uninfected mice at 180 days post-infection. Brucella melitensis evades and blunts adaptive immunity during acute infection and our findings provide potential mechanisms for the deficit observed in responding CD8+ T cells during chronic brucellosis.
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Marina
authors.initials: M
authors.lastname: Durward
authors.forename: Girish
authors.initials: G
authors.lastname: Radhakrishnan
authors.forename: Jerome
authors.initials: J
authors.lastname: Harms
authors.forename: Claire
authors.initials: C
authors.lastname: Bareiss
authors.forename: Diogo
authors.initials: D
authors.lastname: Magnani
authors.forename: Gary A
authors.initials: GA
authors.lastname: Splitter
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000704:Analysis of Variance; D000818:Animals; D002006:Brucellosis / Q000276:immunology* / Q000503:physiopathology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D036781:Fimbriae Proteins / Q000276:immunology*; D005434:Flow Cytometry; D057131:Immune Evasion / Q000276:immunology*; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D036781:Fimbriae Proteins; D007371:Interferon-gamma