Thymic epithelial cells (TECs) form a unique microenvironment that orchestrates T cell differentiation and immunological tolerance. Despite the importance of TECs for adaptive immunity, there is an incomplete understanding of the signalling networks that support their differentiation and survival. We report that the linear ubiquitin chain assembly complex (LUBAC) is essential for medullary TEC (mTEC) differentiation, cortical TEC survival and prevention of premature thymic atrophy. TEC-specific loss of LUBAC proteins, HOIL-1 or HOIP, severely impaired expansion of the thymic medulla and AIRE-expressing cells. Furthermore, HOIL-1-deficiency caused early thymic atrophy due to Caspase-8/MLKL-dependent apoptosis/necroptosis of cortical TECs. By contrast, deficiency in the LUBAC component, SHARPIN, caused relatively mild defects only in mTECs. These distinct roles for LUBAC components in TECs correlate with their function in linear ubiquitination, NFκB activation and cell survival. Thus, our findings reveal dual roles for LUBAC signaling in TEC differentiation and survival.

胸腺上皮细胞 (TEC) 形成独特的微环境，协调 T 细胞分化和免疫耐受。尽管 TEC 对于适应性免疫很重要，但人们对支持其分化和生存的信号网络的了解还不完全。我们报告线性泛素链组装复合物 (LUBAC) 对于髓质 TEC (mTEC) 分化、皮质 TEC 存活和预防胸腺过早萎缩至关重要。 LUBAC 蛋白、HOIL-1 或 HOIP 的 TEC 特异性缺失，严重损害了胸腺髓质和表达 AIRE 的细胞的扩张。此外，HOIL-1 缺陷导致皮质 TEC 的 Caspase-8/MLKL 依赖性细胞凋亡/坏死性凋亡导致早期胸腺萎缩。相比之下，LUBAC 成分 SHARPIN 的缺陷仅在 mTEC 中造成相对轻微的缺陷。 LUBAC 成分在 TEC 中的这些独特作用与其在线性泛素化、NFκB 激活和细胞存活中的功能相关。因此，我们的研究结果揭示了 LUBAC 信号在 TEC 分化和存活中的双重作用。