Comparison of RelB-/- and RelB+/- thymi

Thymic medullary epithelial cell (mTEC) expression of the autoimmune regulator AIRE, and of tissue-specific antigens, is controlled by members of the non-canonical NF-kB signalling pathway, including RelB and NF-kB2. Of the genes in this pathway, RelB-/- mice develop a particularly severe multi-organ autoimmune syndrome, resembling Foxp3-deficiency. RelB-/- mice have medullary atrophy and few mTECs but the mechanism is unknown. We show that RelB is required for expression of medullary chemokines and mTEC AIRE, selection of a diverse peripheral T cell repertoire, and for peripheral Foxp3+ Treg function. Vbeta families of T cells infiltrating diseased peripheral organs and thymic Treg were similarly skewed. Surprisingly, medullary atrophy results from intra-thymic granulocyte infiltration, consequent upon the Th2-mediated autoimmune disease. Dominant tolerance corrects thymic inflammatory disease and loss of thymic function. We demonstrate a reversible RelB-dependent inflammatory mechanism for loss of central tolerance associated with medullary atrophy. Thymi from 4 RelB+/- mice and 3 RelB-/- mice were profiled by microarrays胸腺髓质上皮细胞（medullary thymic epithelial cell，mTEC）对自身免疫调节因子（autoimmune regulator，AIRE）以及组织特异性抗原的表达，受非经典NF-κB信号通路成员的调控，其中包括RelB与NF-κB2。在该通路的相关基因中，RelB敲除（RelB-/-）小鼠会出现尤为严重的多器官自身免疫综合征，其表型与Foxp3缺陷小鼠相似。RelB敲除小鼠存在髓质萎缩以及mTEC数量稀少的问题，但其具体机制尚未阐明。本研究表明，RelB对于髓质趋化因子的表达、mTEC中AIRE的表达、多样化外周T细胞库的筛选，以及外周Foxp3阳性调节性T细胞（regulatory T cell，Treg）的功能均不可或缺。浸润病变外周器官的T细胞以及胸腺Treg的Vβ家族均呈现相似的偏态分布。令人意外的是，髓质萎缩是由胸腺内粒细胞浸润所导致，而该浸润继发于Th2细胞介导的自身免疫性疾病。显性耐受可纠正胸腺炎症性疾病以及胸腺功能的丧失。本研究阐明了一种依赖于RelB的可逆性炎症机制，该机制与髓质萎缩相关的中枢耐受丧失有关。研究人员通过微阵列芯片对4只RelB杂合（RelB+/-）小鼠与3只RelB敲除（RelB-/-）小鼠的胸腺组织进行了表达谱分析。