Lack of the programmed death‐1 receptor renders host susceptible to enteric microbial infection through impairing the production of the mucosal natural killer cell effector molecules

[摘要] Theprogrammeddeath‐1receptorisexpressedonawiderangeofimmuneeffectorcells,includingTcells,naturalkillerTcells,dendriticcells,macrophages,andnaturalkillercells.Inmalignanciesandchronicviralinfections,increasedexpressionofprogrammeddeath‐1byTcellsisgenerallyassociatedwithapoorprognosis.However,itsroleinearlyhostmicrobialdefenseattheintestinalmucosaisnotwellunderstood.Wereportthatprogrammeddeath‐1expressionisincreasedonconventionalnaturalkillercellsbutnotonCD4+,CD8+ornaturalkillerTcells,orCD11b+orCD11c+macrophagesordendriticcellsafterinfectionwiththemousepathogenCitrobacterrodentium.Micegeneticallydeficientinprogrammeddeath‐1ortreatedwithanti–programmeddeath‐1antibodyweremoresusceptibletoacuteentericandsystemicinfectionwithCitrobacterrodentium.Wild‐typebutnotprogrammeddeath‐1–deficientmiceinfectedwithCitrobacterrodentiumshowedsignificantlyincreasedexpressionoftheconventionalmucosalNKcelleffectormoleculesgranzymeBandperforin.Incontrast,naturalkillercellsfromprogrammeddeath‐1–deficientmicehadimpairedexpressionofthosemediators.Consistentwithprogrammeddeath‐1beingimportantforintracellularexpressionofnaturalkillercelleffectormolecules,micedepletedofnaturalkillercellsandperforin‐deficientmicemanifestedincreasedsusceptibilitytoacuteentericinfectionwithCitrobacterrodentium.Ourfindingssuggestthatincreasedprogrammeddeath‐1signalingpathwayexpressionbyconventionalnaturalkillercellspromoteshostprotectionattheintestinalmucosaduringacuteinfectionwithabacterialgutpathogenbyenhancingtheexpressionandproductionofimportanteffectorsofnaturalkillercellfunction...

[学科分类] 生理学

[关键词] Citrobacter rodentium;granzyme B;perforin;attaching/effacing bacteria;PD‐1