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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-?) 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-? production. The B. melitensis-specific CD8(+) T cells that produced IFN-? expressed less IFN-? 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-? 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.

SUBMITTER: Durward-Diioia M

PROVIDER: S-EPMC4645381 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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CD8+ T cell exhaustion, suppressed gamma interferon production, and delayed memory response induced by chronic Brucella melitensis infection.

Durward-Diioia Marina M Harms Jerome J Khan Mike M Hall Cherisse C Smith Judith A JA Splitter Gary A GA

Infection and immunity 20150928 12

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 polyfu ...[more]

PMID: 26416901

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Project description:Brucellosis remains a significant zoonotic threat worldwide. Humans and animals acquire infection via their oropharynx and upper respiratory tract following oral or aerosol exposure. After mucosal infection, brucellosis develops into a systemic disease. Mucosal vaccination could offer a viable alternative to conventional injection practices to deter disease. Using a nasal vaccination approach, the ?znuA B. melitensis was found to confer potent protection against pulmonary Brucella challenge, and reduce colonization of spleens and lungs by more than 2500-fold, with >50% of vaccinated mice showing no detectable brucellae. Furthermore, 10-fold more brucellae-specific, interferon-? (IFN-?)-producing CD8(+) T cells than CD4(+) T cells were induced in the spleen and respiratory lymph nodes. Evaluation of pulmonary and splenic CD8(+) T cells from mice vaccinated with ?znuA B. melitensis revealed that these expressed an activated effector memory (CD44(hi)CD62L(lo)CCR7(lo)) T cells producing elevated levels of IFN-?, tumor necrosis factor-?, perforin and granzyme B. To assess the relative importance of these increased numbers of CD8(+) T cells, CD8(-/-) mice were challenged with virulent B. melitensis, and they showed markedly increased bacterial loads in organs in contrast to similarly challenged CD4(-/-) mice. Only ?znuA B. melitensis- and Rev-1-vaccinated CD4(-/-) and wild-type mice, not CD8(-/-) mice, were completely protected against Brucella challenge. Determination of cytokines responsible for conferring protection showed the relative importance of IFN-?, but not interleukin-17 (IL-17). Unlike wild-type (wt) mice, IL-17 was greatly induced in IFN-?(-/-) mice, but IL-17 could not substitute for IFN-?'s protection, although an increase in brucellae dissemination was observed upon in vivo IL-17 neutralization. These results show that nasal ?znuA B. melitensis vaccination represents an attractive means to stimulate systemic and mucosal immune protection via CD8(+) T-cell engagement.

Dataset Information

CD8+ T cell exhaustion, suppressed gamma interferon production, and delayed memory response induced by chronic Brucella melitensis infection.

Publications

CD8+ T cell exhaustion, suppressed gamma interferon production, and delayed memory response induced by chronic Brucella melitensis infection.

Similar Datasets

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