MHC Ⅰ類分子遞呈修飾后抗原的結(jié)構(gòu)與免疫學(xué)研究的開題報(bào)告

MHCⅠ類分子遞呈修飾后抗原的結(jié)構(gòu)與免疫學(xué)研究的開題報(bào)告摘要：MHCⅠ類分子是通過遞呈抗原來激活CD8+T細(xì)胞并介導(dǎo)細(xì)胞免疫反應(yīng)的關(guān)鍵途徑?？乖f呈分子部分以β2微球蛋白和α鏈組成，不同的共表達(dá)抗原可在其N末端的多態(tài)性域中被特異性結(jié)合并遞呈給T細(xì)胞。然而，MHCⅠ類分子表面的修飾也被確認(rèn)可影響其功能。其中，磷酸化修飾被發(fā)現(xiàn)可調(diào)控抗原遞呈及T細(xì)胞發(fā)育過程。因此，本研究擬通過對(duì)MHCⅠ類分子進(jìn)行磷酸化修飾來研究其在抗原遞呈中的作用，并分析其對(duì)T細(xì)胞免疫應(yīng)答的影響。關(guān)鍵詞：MHCⅠ類分子；抗原遞呈；修飾；磷酸化；T細(xì)胞IntroductionMajorhistocompatibilitycomplex(MHC)ImoleculesareessentialfortheactivationofCD8+T-cell-mediatedcell-mediatedimmuneresponsesbypresentingantigenicpeptidesderivedfromintracellularproteins(1).TheMHCImoleculeiscomposedofβ2-microglobulin(β2m)andanαchain,whichconsistsofthreeextracellulardomains:α1,α2,andα3.Polymorphicregionsontheα-chainenablethespecificbindingandpresentationofarangeofpeptidestoCD8+Tcells(1,2).AlthoughthefunctionalrolesofMHCImoleculesinantigenpresentationarewellestablished,recentstudieshavealsoshownthatpost-translationalmodification(PTM)ofMHCImoleculescanaffecttheirantigenpresentingcapabilityandT-cellimmunogenicity(3,4).PTMssuchasphosphorylationhavebeenidentifiedaskeyregulatorsofMHCIantigenpresentationandT-celldevelopment(4-6).AnalysisofMHCImoleculesfromT-celldepletedmicerevealedthatasignificantportionofMHCImoleculesarephosphorylatedattyrosineresidues(6).FunctionalstudieshaveshownthatthisphosphorylationcanenhanceantigenpresentationbypromotingMHCIassociationwithchaperones,stabilizingpeptidebinding,andenhancingT-cellactivation(5,7,8).Additionally,phosphorylationofMHCImoleculeshasbeenshowntoregulateT-celldevelopment,withlossofphosphorylationleadingtodecreasedpositiveselectionofthymocytes(4).However,thepreciseroleofMHCIphosphorylationinantigenpresentationandT-cellimmunogenicityremainspoorlyunderstood.Therefore,thisstudyproposestoinvestigatetheeffectsofMHCIphosphorylationonantigenpresentationandT-cellimmuneresponsesthroughtheuseofinvitrotechniques.Specifically,MHCImoleculeswillbepurifiedfrommurinetissuesandphosphorylatedinvitro.ThesemodifiedMHCImoleculeswillthenbeassessedfortheirabilitytopresentantigenicpeptidesandstimulateT-cellactivationusingavarietyofimmunecellassays.ObjectivesTheobjectiveofthisstudyistoinvestigatetheroleofMHCIphosphorylationinantigenpresentationandT-cellimmuneresponses.Specifically,thisstudyaimsto:1.PurifyMHCImoleculesfrommurinetissues.2.PhosphorylateMHCImoleculesusinginvitrotechniques.3.DeterminetheantigenpresentingcapabilityofphosphorylatedMHCImolecules.4.AnalyzetheeffectsofMHCIphosphorylationonT-cellactivationandimmuneresponses.Methods1.MHCIpurification:MHCImoleculeswillbepurifiedfrommurinetissuesusingaffinitychromatographywithanti-MHCIantibodies.2.MHCIphosphorylation:PurifiedMHCImoleculeswillbephosphorylatedinvitrousingrecombinanttyrosinekinases.3.Antigenpresentationassays:PhosphorylatedMHCImoleculeswillbeassessedfortheirabilitytopresentantigenicpeptidesusingavarietyofimmunecellassays,includingT-cellproliferation,cytokineproduction,andcytotoxicityassays.4.T-cellactivationassays:TheeffectsofMHCIphosphorylationonT-cellactivationandimmuneresponseswillbeanalyzedusingflowcytometryandELISAassays.ExpectedOutcomesThisstudyisexpectedtoprovidenewinsightsintotheroleofMHCIphosphorylationinantigenpresentationandT-cellimmuneresponses.Specifically,itisanticipatedthatphosphorylationofMHCImoleculeswillenhancetheirantigenpresentingcapabilityandpromoteT-cellactivation,leadingtoenhancedimmuneresponses.Thisstudyisalsoexpectedtorevealtheunderlyingmolecularmechanismsresponsiblefortheseeffects,whichmayhaveimportantimplicationsforthedevelopmentofnewimmunotherapiesthattargetMHCImolecules.ConclusionMHCImoleculesarecentraltotheactivationofCD8+T-cell-mediatedcell-mediatedimmuneresponses.Post-translationalmodificationssuchasphosphorylationhavebeenshowntoregulateMHCIantigenpresentationandT-celldevelopment.Therefor