active evasion of ctl mediated killing and low quality responding cd8+ t cells contribute to persistence of brucellosis主动逃避细胞毒性t淋巴细胞介导的杀戮和低质量的cd8 + t细胞的反应造成持久性的布鲁氏菌病.pdfVIP

Active Evasion of CTL Mediated Killing and Low Quality Responding CD8+ T Cells Contribute to Persistence of Brucellosis 1 2 2 2 2 Marina Durward , Girish Radhakrishnan , Jerome Harms , Claire Bareiss , Diogo Magnani , Gary A. Splitter2* 1 Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America, 2 Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America 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-c with TNFa and/or IL-2, a hallmark of exhaustion. When investigating the expression of these 3 cytokines individually, we observed significant IFN-c expression at 90 and 180 days post-infection. TNFa expression did not significantly exceed