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CD8+ T cell exhaustion, suppressed gamma interferon production, and delayed
memory response induced by chronic Brucella melitensis infection
#MMPMID26416901
Durward-Diioia M
; Harms J
; Khan M
; Hall C
; Smith JA
; Splitter GA
Infect Immun
2015[Dec]; 83
(12
): 4759-71
PMID26416901
show ga
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.
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