Irla Magali, Hugues Stéphanie, Gill Jason, Nitta Takeshi, Hikosaka Yu, Williams Ifor R, Hubert François-Xavier, Scott Hamish S, Takahama Yousuke, Holländer Georg A, Reith Walter
University of Geneva Medical School, CMU, 1 Rue Michel-Servet, CH-1211, Geneva, Switzerland.
Immunity. 2008 Sep 19;29(3):451-63. doi: 10.1016/j.immuni.2008.08.007.
Medullary thymic epithelial cells (mTECs) are specialized for inducing central immunological tolerance to self-antigens. To accomplish this, mTECs must adopt a mature phenotype characterized by expression of the autoimmune regulator Aire, which activates the transcription of numerous genes encoding tissue-restricted self-antigens. The mechanisms that control mature Aire(+) mTEC development in the postnatal thymus remain poorly understood. We demonstrate here that, although either CD4(+) or CD8(+) thymocytes are sufficient to sustain formation of a well-defined medulla, expansion of the mature mTEC population requires autoantigen-specific interactions between positively selected CD4(+) thymocytes bearing autoreactive T cell receptor (TCR) and mTECs displaying cognate self-peptide-MHC class II complexes. These interactions also involve the engagement of CD40 on mTECs by CD40L induced on the positively selected CD4(+) thymocytes. This antigen-specific TCR-MHC class II-mediated crosstalk between CD4(+) thymocytes and mTECs defines a unique checkpoint in thymic stromal development that is pivotal for generating a mature mTEC population competent for ensuring central T cell tolerance.
髓质胸腺上皮细胞（mTECs）专门用于诱导对自身抗原的中枢免疫耐受。为实现这一点，mTECs必须呈现出以自身免疫调节因子Aire表达为特征的成熟表型，Aire可激活众多编码组织限制性自身抗原的基因的转录。出生后胸腺中控制成熟Aire(+) mTECs发育的机制仍知之甚少。我们在此证明，虽然CD4(+)或CD8(+)胸腺细胞足以维持明确髓质的形成，但成熟mTEC群体的扩增需要携带自身反应性T细胞受体（TCR）的阳性选择CD4(+)胸腺细胞与展示同源自身肽 - MHC II类复合物的mTECs之间的自身抗原特异性相互作用。这些相互作用还涉及阳性选择的CD4(+)胸腺细胞上诱导的CD40L与mTECs上的CD40的结合。CD4(+)胸腺细胞与mTECs之间这种抗原特异性的TCR - MHC II类介导的串扰定义了胸腺基质发育中的一个独特检查点，这对于产生能够确保中枢T细胞耐受的成熟mTEC群体至关重要。
