特異性免疫細胞學習教案

1、會計學1特異性免疫特異性免疫(miny)細胞細胞第一頁，共68頁。第2頁/共68頁第二頁，共68頁。The types and subsets of lymphocytes 55%25%10%10%5%第3頁/共68頁第三頁，共68頁。第4頁/共68頁第四頁，共68頁。 來源于骨髓來源于骨髓在胸腺（在胸腺（thymusthymus）內(nèi)發(fā)育）內(nèi)發(fā)育成熟成熟移行至外周淋巴組織移行至外周淋巴組織執(zhí)行特異性細執(zhí)行特異性細胞免疫應(yīng)答，參與對胞免疫應(yīng)答，參與對TDTD抗原的體液免疫應(yīng)答抗原的體液免疫應(yīng)答。 重要事件重要事件 * * 功能性功能性TCRTCR形成（基因重排）；形成（基因重排）；* * 陽性選

2、擇陽性選擇(xunz)(xunz)* * 陰性選擇陰性選擇(xunz)(xunz)。意義意義 * * 獲得功能性與多樣性的獲得功能性與多樣性的TCRTCR； * * 獲得獲得MHCMHC的限制性；的限制性； * * 獲得對自身抗原的耐受性。獲得對自身抗原的耐受性。T淋巴細胞的發(fā)育淋巴細胞的發(fā)育(fy)第5頁/共68頁第五頁，共68頁。The thymus is required for T cell maturationAthymic mice (nude) and humans (DiGeorge syndrome)are immunodeficient due to a lack of T

3、 cellsNeonatal thymectomyNo mature T cellsIn adultNo thymectomyMature T cellsIn adult第6頁/共68頁第六頁，共68頁。The thymus matures T cells afterbirth, but early in lifeRemove ThymusMature T & B cellsAdultNeonateNo T cellsMature B cells presentT cells not yet left thymusThe thymus is needed to generate mat

4、ure T cells第7頁/共68頁第七頁，共68頁。The thymusLobulated structure with a STROMA of epithelial cells & connective tissueStroma provides a microenvironment for T cell development & selectionLobules differentiated into an outer CORTEX & inner MEDULLA, both filled with bone-marrow-derived THYMOCYTES

5、CortexMedullaCorticalepithelial cellMedullaryepithelial cellDendritic cellThymocyteMacrophage* 胸腺基質(zhì)細胞：黏附胸腺細胞，產(chǎn)生細胞因子（IL-1,6,7)和胸腺激素促進(cjn)T細胞分化發(fā)育* DC、巨噬細胞和胸腺上皮細胞：向T細胞提呈抗原肽/MHC分子第8頁/共68頁第八頁，共68頁。T Cell Development in ThymusT Cell Development in Thymus第9頁/共68頁第九頁，共68頁。Mousethymus5 x 107 per dayT cells

6、mature in the thymus but most die there.98% of cells die in the thymus without inducing any inflammation or any change in the size of the thymus.Thymic macrophages phagocytose apoptotic thymocytes.2 x 106 per dayConstant1-2 x 108cells第10頁/共68頁第十頁，共68頁。YTYYTTAPCHarmfulUselessUsefulYT?Positivelyselect

7、NegativelyselectWholly self-reactive and useless T cells are removed MHC-restricted are retainedTHYMUSYTYTYYYYTTYYTTYYYTTTYYYYTYTTTRandom TcRrepertoireensures diversityYTYTYTNeglect第11頁/共68頁第十一頁，共68頁。98%T cell development is marked by cell surfacemolecule changesAs T cells mature in the thymus they

8、change their expression of TcR-associated molecules and co-receptors.These changes can be used as markers of their stage of maturation CD3/TcR-CD4-, 8-DoublenegativeCD3+TcR-chain +pre-TcR+ (pTCD4+, 8+LargedoublepositiveCD3+TcR +CD4+CD8+SmalldoublepositiveTcR+CD3+CD4-, 8-CD3+TcR +CD4+SinglepositiveCD

9、3+TcR +CD8+Singlepositive第12頁/共68頁第十二頁，共68頁。How are MHC restricted cells selected from the immature T cell repertoire?TcR OKMHC OKTcR wrongMHC OKUsefulUseless第13頁/共68頁第十三頁，共68頁。T細胞不能識別(shbi)胸腺皮質(zhì)上皮細胞提呈的肽/MHC復(fù)合物，即發(fā)生凋亡。第14頁/共68頁第十四頁，共68頁。DP細胞的CD4結(jié)合皮質(zhì)胸腺上皮細胞的MHCII類分子，CD8丟失(dis)，成為CD4T細胞；而CD8結(jié)合MHCI類分子，則CD

10、4丟失(dis)，成為CD8T細胞。第15頁/共68頁第十五頁，共68頁。DP細胞(xbo)TCR識別經(jīng)陽性選擇的T細胞與髓質(zhì)DC和巨噬細胞提呈的自身肽/MHC復(fù)合物高親和力結(jié)合，則發(fā)生(fshng)凋亡。第16頁/共68頁第十六頁，共68頁。第17頁/共68頁第十七頁，共68頁。T細胞細胞(xbo)的發(fā)育的發(fā)育第18頁/共68頁第十八頁，共68頁。第19頁/共68頁第十九頁，共68頁。第20頁/共68頁第二十頁，共68頁。第21頁/共68頁第二十一頁，共68頁。immunoreceptor tyrosine-based activation motif第22頁/共68頁第二十二頁，共68頁。

11、T cell co-receptor moleculesCD8MHC Class IMHC Class II32TcRTcRCD4Lck PTKLck PTKCD4 and CD8 can increase the sensitivity of T cells to peptide antigen MHC complexes by 100 fold第23頁/共68頁第二十三頁，共68頁。第24頁/共68頁第二十四頁，共68頁。Inhibition of T cell activation by CTLA-4 第25頁/共68頁第二十五頁，共68頁。LFA-1/ICAM-1CD2/LFA-3第2

12、6頁/共68頁第二十六頁，共68頁。第27頁/共68頁第二十七頁，共68頁。第28頁/共68頁第二十八頁，共68頁。第29頁/共68頁第二十九頁，共68頁。第30頁/共68頁第三十頁，共68頁。 T TC CR R T T 細細胞胞T TC CR R T T 細細胞胞T TC CR R 多多樣樣性性分分布布 外外周周血血 組組織織表表型型 C CD D3 3+ + C CD D2 2+ + C CD D4 4+ + C CD D8 8- - C CD D4 4- - C CD D8 8+ + C CD D4 4- - C CD D8 8- -識識別別抗抗原原M MH HC C 限限制制性性輔輔

13、助助細細胞胞殺殺傷傷細細胞胞極極高高6 60 0- -7 70 0% %外外周周淋淋巴巴組組織織1 10 00 0% %6 60 0- -6 65 5% %3 30 0- -3 35 5% % 5 5% %8 8- -1 17 7 個個氨氨基基酸酸經(jīng)經(jīng)典典M MH HC CT Th hT Tc c低低5 5- -1 15 5% %粘粘膜膜上上皮皮1 10 00 0% % 5 50 0% %簡簡單單多多肽肽、H HS SP P、脂脂類類、多多糖糖M MH HC C 類類似似分分子子T Tc c T TC CR R T T第31頁/共68頁第三十一頁，共68頁。 CD4+T CD4+T與與CD8+

14、TCD8+T細胞細胞(xbo)(xbo)的比較的比較 CD4+T CD4+T細胞細胞(xbo) CD8+T(xbo) CD8+T細細胞胞(xbo)(xbo)表型表型 CD3+CD4+CD8- CD3+CD8+CD4- CD3+CD4+CD8- CD3+CD8+CD4-識別抗原肽識別抗原肽 13 1318AA 818AA 810AA10AAMHCMHC限制性限制性 MHC-II MHC-II類分子類分子 MHC-I MHC-I類分子類分子Th + -Th + -Tc + +Tc + +第32頁/共68頁第三十二頁，共68頁。CD8CD8MHC-ICD4CD4MHC-IICD4CD4MHC-II第

15、33頁/共68頁第三十三頁，共68頁。第34頁/共68頁第三十四頁，共68頁。Cytokine profile of helper T lymphocyte subsetsTh1Th2Th0IL-3GM-CSFIL-4IL-5IL-6IL-10TGF-IL-3GM-CSFIL-2IFN-TNFTNF-High IL-2Low IL-4IFN-CCR3CCR5IL-4IL-12IFN-第35頁/共68頁第三十五頁，共68頁。Effector functions of Th1 cellspCTLCTLLysis of targetInduction of CTL differentiationIF

16、N-Inflammatory Th1T cellTh1MacrophageActivated macrophageKilling of intracellular bacteriaIL-12IFN-IL-2第36頁/共68頁第三十六頁，共68頁。Th2Th0V D J C CIg isotype switch factorIgGV D J CIgECD40L-CD40 + IL-4BEffector functions of Th2 cellsIL-4 also enhances IgM, huIgG4 and muIgG1第37頁/共68頁第三十七頁，共68頁。Counter regulat

17、ion of Th cell subsetsBalanced responseTh2IFN-IL-10-Th1Th2 DominantTh1IL-10Th2-Th1 DominantTh2Th1IFN-Humoral immunityCell mediated immunity第38頁/共68頁第三十八頁，共68頁。Th1 & Th2 polarisation may be influencedby the type of infectionIL-12IFN-MacrophageNK cellIL-4Mast cellTh1Th2Th0IFN-第39頁/共68頁第三十九頁，共68頁。特

18、征：特征：-抑制抑制CD4T和和CD8T 細胞細胞(xbo) 活化與活化與增殖增殖-直接接觸性抑制；直接接觸性抑制；-CTLA-4, mTGF-b;-下調(diào)下調(diào)APC的的B7第40頁/共68頁第四十頁，共68頁。第41頁/共68頁第四十一頁，共68頁。第42頁/共68頁第四十二頁，共68頁。第43頁/共68頁第四十三頁，共68頁。第44頁/共68頁第四十四頁，共68頁。第45頁/共68頁第四十五頁，共68頁。Suppressor cells?CD4+ThCD8+Ts+-TcR-containing, MHC-restricted“suppressor factors”TcR-containing

19、, MHC-restricted“helper factors”1970s & 1980s mechanism (now superseded)T cells produce cytokines that inhibit the induction of T cellsHighIL-10CD4Tr1IL-10TGF-CD8No IL-2or IL-41990s mechanism第46頁/共68頁第四十六頁，共68頁。第47頁/共68頁第四十七頁，共68頁。第48頁/共68頁第四十八頁，共68頁。The discovery of B cell immunity1954 - Bruce

20、Glick, Ohio State UniversityStudies on the function of a lymphoid organ in the cloacal region of the chicken the bursa of Fabricius Bursectomy no apparent effectBursectomised chickens were later used in experiments to raise antibodies to Salmonella antigens None of the bursectomised chickens made an

21、ti-Salmonella antibodiesBursa was later found to be the organ in which antibody producing cells developed antibody producing cells were thereafter called B cellsMammals do not have a bursa of Fabricius第49頁/共68頁第四十九頁，共68頁。 B細胞在胎肝和骨髓發(fā)育成熟細胞在胎肝和骨髓發(fā)育成熟進入外周淋巴進入外周淋巴組織組織 遇到抗原遇到抗原在生發(fā)中心增殖、突變、選擇在生發(fā)中心增殖、突變、選擇 抗

22、體親和力成熟，抗體親和力成熟，Ig類型轉(zhuǎn)化，產(chǎn)生記憶類型轉(zhuǎn)化，產(chǎn)生記憶B和漿細和漿細胞胞 產(chǎn)生抗體，介導體液免疫產(chǎn)生抗體，介導體液免疫主要事件主要事件* 功能性功能性BCR形成形成(xngchng)（基因重排，骨髓）（基因重排，骨髓）* 陰性選擇（骨髓）陰性選擇（骨髓）* 陽性選擇（生發(fā)中心）陽性選擇（生發(fā)中心）意義意義* BCR多樣性多樣性* 獲得自身耐受獲得自身耐受* BCR與抗體親和力成熟、與抗體親和力成熟、Ig類型轉(zhuǎn)換、記類型轉(zhuǎn)換、記 憶憶B細胞和漿細胞的產(chǎn)生細胞和漿細胞的產(chǎn)生第50頁/共68頁第五十頁，共68頁。Transfer foetalliver cellsOrigin of

23、B cells and organ of B cellmaturationNo MatureB cellsAfter birth, development continues in the bone marrowNormal bone marrowDefective bone marrowMature B cellsin peripheryB cell development starts in the foetal liver第51頁/共68頁第五十一頁，共68頁。The stages of B cell development are distinguished by the expres

24、sion of immunoglobulin chains and particular cell-surface proteins.陰性(ynxng)選擇生發(fā)(shngf)中心第52頁/共68頁第五十二頁，共68頁。第53頁/共68頁第五十三頁，共68頁。第54頁/共68頁第五十四頁，共68頁。Primary Follicles becomesecondary follicleswhen germinal centres developDark zoneLight zoneBTFollicular dendriticcells capture antigen on its surface,

25、present to B cellsGerminal Centre Microanatomy1. B cells (centroblasts) downregulatesurface Ig, proliferate, somatically hypermutate their Ig V genes.AFFINITY MATURATION2. B cells (centrocytes) upregulatesurface Ig, stop dividing and recognize antigen on FDC,receive costimulatory signalsfrom Th cell

26、s3. Apoptosis ofself-reactive &unselected cells4. Selected cells leave lymphnode as memorycells or plasma cellsB第55頁/共68頁第五十五頁，共68頁。第56頁/共68頁第五十六頁，共68頁。第57頁/共68頁第五十七頁，共68頁。第58頁/共68頁第五十八頁，共68頁。第59頁/共68頁第五十九頁，共68頁。Co-stimulatory molecules on B cells 第60頁/共68頁第六十頁，共68頁。第61頁/共68頁第六十一頁，共68頁。第62頁/共68頁

27、第六十二頁，共68頁。CD5Two B cell lineagesBB cell precursorBMature B cellB2 cellsPlasma cellYYYYYYYYYPCIgGBYYYYYYYYYYYYYYYYYYYYIgM - no other isotypesBDistinct B cellprecursor?B1 cellsPrimitive B cells found in pleura and peritoneum第63頁/共68頁第六十三頁，共68頁。Comparison of B-1 and B-2 cell propertiesPropertyB-1 cellsB-2 cellsV region repertoireRestrictedDiverseLocationPeritoneum/pleuraEverywhere