Center for Immunology and Department of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, MN, 55455.
Eur J Immunol. 2021 May;51(5):1080-1088. doi: 10.1002/eji.202048996. Epub 2021 Feb 23.
TCRαβ CD8α CD8β intestinal intraepithelial lymphocytes (CD8αα IEL) are gut T cells that maintain barrier surface homeostasis. Most CD8αα IEL are derived from thymic precursors (IELp) through a mechanism referred to as clonal diversion. In this model, self-reactive thymocytes undergo deletion in the presence of CD28 costimulation, but in its absence undergo diversion to the IEL fate. While previous reports showed that IELp were largely β2m dependent, the APC that drive the development of these cells are poorly defined. We found that both CD80 and CD86 restrain IELp development, and conventional DCs play a prominent role. We sought to define a CD80/86 negative, MHCI positive APC that supports the development to the IEL lineage. Chimera studies showed that MHCI needs to be expressed on hematopoietic APC for selection. As thymic hematopoietic APC are heterogeneous in their expression of MHCI and costimulatory molecules, we identified four thymic APC types that were CD80/86 and MHCI . However, selective depletion of β2m in individual APC suggested functional redundancy. Thus, while hematopoietic APC play a critical role in clonal diversion, no single APC subset is specialized to promote the CD8αα IEL fate.
TCRαβ CD8α CD8β 肠上皮内淋巴细胞（CD8αα IEL）是维持屏障表面稳态的肠道 T 细胞。大多数 CD8αα IEL 来自于胸腺前体（IELp），通过一种称为克隆转移的机制。在这个模型中，自身反应性的胸腺细胞在 CD28 共刺激存在的情况下发生删除，但在缺乏共刺激的情况下发生转移到 IEL 命运。尽管先前的报告表明 IELp 主要依赖于β2m，但驱动这些细胞发育的 APC 尚未明确。我们发现 CD80 和 CD86 都限制了 IELp 的发育，而传统的 DC 起着突出的作用。我们试图定义一种 CD80/86 阴性、MHCI 阳性的 APC，支持 IEL 谱系的发育。嵌合体研究表明，MHCI 需要在造血 APC 上表达才能进行选择。由于胸腺造血 APC 在 MHCI 和共刺激分子的表达上存在异质性，我们鉴定了四种表达 CD80/86 和 MHCI 的胸腺 APC 类型。然而，对单个 APC 中β2m 的选择性耗竭表明存在功能冗余。因此，虽然造血 APC 在克隆转移中起着关键作用，但没有一个 APC 亚群专门促进 CD8αα IEL 命运。
