CMI2014-Chapter-8-Lymphocyte development

Cellular and Molecular Immunology,Xian-Hui HeDepartment of ImmunobiologyJinan University2014-11,1,Chapter 8 The Development and Survival of Lymphocytes,Development of B lymphocytes. The development of T lymphocytes in the thymus. Positive and negative selection of T cells. Survival and maturation of lymphocytes in peripheral lymphoid tissues.,Part III The development of mature lymphocyte receptor repertoires,2,中枢耐受的形成,1. Development of B lymphocytes. B淋巴细胞的发育,3,Development of B lymphocytes.,8-1 B淋巴细胞由骨髓中的造血干细胞 (HSC) 所产生. hematopoietic stem cells (HSC) .,骨髓中产生BCR,骨髓中阴性选择,在外周活化,成为浆细胞和记忆细胞,4,Development of B lymphocytes.,B细胞早期发育依赖于骨髓基质细胞 (stromal cells) .,骨髓基质细胞表达B细胞发育所需的IL-7、CXCL12、VCAM-1、SCF,5,晚期祖B细胞,多能干细胞,前B细胞,未成熟B细胞,早期祖B细胞,淋巴样干细胞,Development of B lymphocytes.,8-2 B细胞发育始于重链基因的重排, 重链与替代轻链组成前B受体 (Pre-B receptor).,6,大前B细胞,多能干细胞,小前B细胞,未成熟B细胞,晚期祖B细胞,早期祖B细胞,成熟B细胞,重链重排,前B受体,轻链重排,IgM表达,IgD表达,Development of B lymphocytes.,8-3 前B受体检测重链的成功重排, 从而传递信号触发轻链重排，完成Pro-B到Pre-B的转换.,7,Development of B lymphocytes.,8,Development of B lymphocytes.,8-4 前B受体传递信号抑制重链基因的进一步重排，完成等位基因排斥(allelic exclusion).,9,Development of B lymphocytes.,8-5 Pre-B细胞重排轻链基因，在细胞表面表达Ig. 轻链等位基因排斥; isotypic exclusion: or 轻链基因可以重复重排，直到产生有功能的轻链蛋白,10,Development of B lymphocytes.,8-6 未成熟的前B细胞在离开骨髓前检测自身反应性. 阴性选择：不与自身抗原反应的B细胞发育成熟中枢耐受 (central tolerance)形成的主要机制cell death by apoptosis or clonal deletion (克隆删除)the production of a new receptor by a process known as receptor editing (受体编辑)the induction of a permanent state of unresponsiveness, or anergy, to antigen (失能)immunological ignorance (免疫忽视),11,12,无自身反应性,多价自身分子,可溶自身分子,低亲和力非交联自身分子,成熟B细胞,凋亡或产生无自身反应性成熟B细胞,失能B细胞,克隆忽略成熟B细胞,2. The development of T lymphocytes in the thymus. T淋巴细胞在胸腺中的发育,13,The development of T lymphocytes in the thymus.,14,The development of T lymphocytes in the thymus.,8-7 T细胞的祖细胞源于骨髓，但所有重要发育事件在胸腺进行. 在胸腺中发育的T细胞称为胸腺细胞(thymocytes),髓质,皮质,(基质stroma),(基质stroma),15,The development of T lymphocytes in the thymus.,在胸腺中发育的T细胞称为胸腺细胞(thymocytes)裸鼠(Nude mice): 上皮细胞终末分化所需的转录因子Foxn1基因缺陷, 无胸腺（无T细胞，有B细胞）Human DiGeorge syndrome: 无胸腺（无T细胞，有B细胞）严重联合免疫缺陷(SCID)：无T、无B （抗原受体基因重排缺陷）,16,The development of T lymphocytes in the thymus.,8-8 T细胞前体在胸腺大量扩增，但大部分死亡. 98% thymocytes 凋亡,17,The development of T lymphocytes in the thymus.,8-9 不同细胞表面分子的表达显示胸腺细胞处于不同发育阶段.,18,19,T细胞受体(TCR)的发育:TCR 基因先重排，成功重排的链与替代轻链pT组成pre-TCRTCR 基因随后重排，表达有功能TCR， 经历选择过程。,成功重排的链与替代轻链pT组成pre-TCR,增殖,双阴性细胞,双阳性细胞,单阳性细胞,CD4,CD8,阳性选择,TCR重排,TCR的链开始重排,阴性选择,The development of T lymphocytes in the thymus.,8-10 不同发育阶段的胸腺细胞位于胸腺的特定部分.,20,The development of T lymphocytes in the thymus.,8-11 :或: T细胞是从一个共同的祖细胞发育而来.,21,3. Positive and negative selection of T cells. T细胞的阳性选择和阴性选择,22,Positive and negative selection of T cells.,8-15 胸腺基质细胞的MHC选择了成熟T细胞谱系，能识别同样MHC提呈的外来抗原.,23,Positive and negative selection of T cells.,8-16 只有其受体能与自身肽:自身MHC结合的胸腺细胞才能在胸腺基质细胞作用下存活并成熟.,24,MHCa限制性转基因TCR,MHCb限制性转基因TCR,Positive and negative selection of T cells.,8-18 阳性选择(positive selection)协调CD4或CD8共受体表达，并确定T细胞的功能, 即决定了T细胞识别的MHC限制性.,25,识别MHC I类转基因TCR,识别MHC I类转基因TCR,Positive and negative selection of T cells.,阳性选择决定了T细胞的功能,CD4+CD8 helper T cellsCD4+CD8 cytotoxic T cellsCD4+CD8CD25+: natural Treg cells,thymocytes,26,Positive and negative selection of T cells.,8-19 胸腺皮质上皮细胞介导发育中的胸腺细胞的阳性选择.,27,上皮细胞正常表达MHC II,上皮细胞不表达MHC II的突变体,Positive and negative selection of T cells.,28,突变体通过转基因使胸腺上皮细胞表达MHC II,突变体通过转基因使胸腺上皮细胞表达不能与CD4结合的MHC II,Positive and negative selection of T cells.,8-20 能强烈地与普遍存在的自身肽反应的T细胞在胸腺中被删除，这个现象称为阴性选择阴性选择 (negative selection) occur at either double-positive or single-positive stage.胸腺髓质细胞在AIRE转录因子作用下表达大多数组织特异性蛋白(如胰岛素).,29,Positive and negative selection of T cells.,8-21 阴性选择主要由骨髓产生的抗原提呈细胞所介导. 阴性选择由胸腺髓质和皮质内的DC和M介导.胸腺髓质细胞在AIRE作用下表达大多数组织特异性蛋白(如胰岛素).阴性选择导致中枢耐受的形成.,30,Positive and negative selection of T cells.,8-22 阳性选择和阴性选择的特异性和信号强度必须不同. Affinity hypothesis.,31,4. Survival and maturation of lymphocytes in peripheral lymphoid tissues.外周淋巴组织中淋巴细胞的生存和发育,32,Survival and maturation of lymphocytes in peripheral lymphoid tissues.,8-23 不同淋巴细胞定位于外周组织的不同部位. 淋巴结的滤泡及生发中心(Germinal center)为B细胞区淋巴结的T细胞区,33,Survival and maturation of lymphocytes in peripheral lymphoid tissues.,8-24 外周淋巴样组织的发育受淋巴样组织诱导细胞和TNF家族蛋白所调控.,34,Survival and maturation of lymphocytes in peripheral lymphoid tissues.,8-25 淋巴细胞归巢（homing）至特定淋巴样组织是由趋化因子所介导.,35,Survival and maturation of lymphocytes in peripheral lymphoid tissues.,8-26 淋巴细胞在外周首次遭遇足够量自身抗原时被删去或灭活. 外周耐受的形成机制: deletion、anergy活化诱导的细胞死亡 (activation-induced cell death, AICD),36,Survival and maturation of lymphocytes in peripheral lymphoid tissues.,8-27 到达脾脏的B细胞快速更新，其成熟和存活需接受BCR和细胞因子信号.,37,Survival and maturatio