title: CD8+ T cell exhaustion, suppressed gamma interferon production, and delayed memory response induced by chronic Brucella melitensis infection.
abstract: Brucella melitensis is a well-adapted zoonotic pathogen considered a scourge of mankind since recorded history. In some cases, initial infection leads to chronic and reactivating brucellosis, incurring significant morbidity and economic loss. The mechanism by which B. melitensis subverts adaptive immunological memory is poorly understood. Previous work has shown that Brucella-specific CD8(+) T cells express gamma interferon (IFN-γ) and can transition to long-lived memory cells but are not polyfunctional. In this study, chronic infection of mice with B. melitensis led to CD8(+) T cell exhaustion, manifested by programmed cell death 1 (PD-1) and lymphocyte activation gene 3 (LAG-3) expression and a lack of IFN-γ production. The B. melitensis-specific CD8(+) T cells that produced IFN-γ expressed less IFN-γ per cell than did CD8(+) cells from uninfected mice. Both memory precursor (CD8(+) LFA1(HI) CD127(HI) KLRG1(LO)) and long-lived memory (CD8(+) CD27(HI) CD127(HI) KLRG1(LO)) cells were identified during chronic infection. Interestingly, after adoptive transfer, mice receiving cells from chronically infected animals were able to contain infection more rapidly than recipients of cells from acutely infected or uninfected donors, although the proportions of exhausted CD8(+) T cells increased after adoptive transfer in both challenged and unchallenged recipients. CD8(+) T cells of challenged recipients initially retained the stunted IFN-γ production found prior to transfer, and cells from acutely infected mice were never seen to transition to either memory subset at all time points tested, up to 30 days post-primary infection, suggesting a delay in the generation of memory. Here we have identified defects in Brucella-responsive CD8(+) T cells that allow chronic persistence of infection.
authors.affiliation: Department of Microbiology and Immunology, Midwestern University, Glendale, Arizona, USA Department of Pathobiological Sciences, University of Wisconsin-Madison School of Veterinary Medicine, Madison, Wisconsin, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Durward-Diioia
authors.affiliation: Department of Pathobiological Sciences, University of Wisconsin-Madison School of Veterinary Medicine, Madison, Wisconsin, USA.
authors.forename: Jerome
authors.initials: J
authors.lastname: Harms
authors.affiliation: Cellular and Molecular Pathology Training Program, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Khan
authors.affiliation: Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Cherisse
authors.initials: C
authors.lastname: Hall
authors.affiliation: Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Smith
authors.affiliation: Department of Pathobiological Sciences, University of Wisconsin-Madison School of Veterinary Medicine, Madison, Wisconsin, USA splitter@svm.vetmed.wisc.edu.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Splitter
mesh_terms: D056704:Adaptive Immunity; D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D017347:Brucella melitensis / Q000276:immunology* / Q000472:pathogenicity; D002006:Brucellosis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology / Q000473:pathology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology / Q000473:pathology / Q000637:transplantation; D002908:Chronic Disease; D017635:Clonal Anergy; D005260:Female; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma; D000093322:Lymphocyte Activation Gene 3 Protein