Ahallmarkoftheimmunesystemisitsabilitytomountamoreeffectiveandrapidresponseagainstsecondary exposuretoapathogen.Themechanismsbywhichtheadaptiveimmunesystemaccomplishesthistask centeraroundDNArearrangementsandselectionofthemosteffectively-respondingcells.However,ithas recentlybecomeevidentthatinnateimmunecellsalsoexhibitmemory,andthatunlikeadaptiveimmunecells, innateimmunecellscanexhibitmemorytowardsdifferentpathogensaswellasthesameoneencountered duringtheinitialexposure.Thisprocess,calledtrainedimmunity,canpresentasenhancedprotectionfrom heterologousinfectionfollowingvaccination.Ontheotherhand,diseasescharacterizedbyinflammationmay beexacerbatedbytheinductionoftrainedimmunity.Preliminaryworkfromourlabaswellasothers?has suggestedthattrainedimmunityisdrivenbyalteredtranscriptionalresponses,withinheritedchromatin structuresplayinganimportantroleinpropagatingmemoryacrosscelldivisions.Ourstudieshavedefineda subsetofgenesthatdisplaymorerapidinductionuponasecondexposuretoastimulusinalymphocyte-to- macrophagetransdifferentiationmodel.These?memory?genesdisplayareductionintrimethylationoflysine 27ofhistoneH3(H3K27me3),andinhibitingH3K27me3demethylationresultsinimpairedmemoryformation attheseloci.Wehaveundertakenapilotunbiasedscreenforadditionalchromatinfactorsthatcouldinfluence memoryformation,andhaveidentified23genesthatscoredhighlyandarecurrentlybeingvalidated. Inthiswork,weplantoextendourfindingstomacrophagesandNKcells,twocelltypesoftheinnateimmune systemthoughttoexhibitmemory.Wewillestablishprotocolstoelicitamemoryresponseinthesecells,using stimulithatmimicpathogenexposureorcytokinesignaling,andexaminewhichgenesexhibitmemoryineach context.Usingchromatinimmunoprecipitationapproaches,wewillidentifychromatinmodificationsthat accompanytheinductionoftranscriptionalmemory,andwewillemploysmall-moleculeandshRNA-based screeningapproachestoidentifychromatinregulatorsresponsiblefortheestablishmentormaintenanceof memory.Finally,wewillextendourresultstoamousemodelofdiet-inducedobesity,apathologyexacerbated byinflammationofadiposetissuesbypro-inflammatorymacrophageactivity.Wewillexaminewhether macrophagetranscriptionalmemoryplaysaroleinasecondinductionofobesityfollowingaperiodofweight loss.Weexpectourstudiestoelucidatethechromatin-basedmolecularmechanismsunderlyingthe establishmentandmaintenanceoftranscriptionalmemory,andrevealhowthesemechanismsplayarolein thepathologicalcontextofdiet-inducedobesity.

Public Health Relevance

Justlikeweashumanscanlearnfrompastexperiences,cellswithinourbodyalsohavethecapabilitytolearn afterexposuretovariousstimuliandtomaintainthismemorytoallowforcellularadaptation.Forexample,as cellsoftheimmunesystemfightoffnewinfections,theylearnfromthisexposuretoenableaquickerand betterresponseinthefuture.Intheproposedsetofexperiments,wewillexplorethedifferentmolecules involvedinestablishingcellularmemory,andhopetoexplainhowmemorycanbothhelphumansmorereadily fightdisease,andalsocontributetopathologiessuchasobesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI130737-02
Application #
9413990
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Jiang, Chao
Project Start
2017-01-18
Project End
2019-04-30
Budget Start
2018-01-01
Budget End
2019-04-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code