Department of Immunology, Harvard Medical School, Boston, MA 02115.
Proc Natl Acad Sci U S A. 2022 Nov 29;119(48):e2215474119. doi: 10.1073/pnas.2215474119. Epub 2022 Nov 21.
Medullary thymic epithelial cells (mTECs) are essential for the establishment of T cell central tolerance. The transcription factor Aire plays a key role in this process, but other factors remain understudied. We found that a small population of mTECs expressed the coinhibitory receptor cytotoxic T lymphocyte-associated protein 4 (CTLA-4). These CTLA-4 cells were detectable in perinates, peaked around young adulthood and expanded sixfold in the absence of Aire. Single-cell transcriptomics revealed CTLA-4 mTECs to express a distinct gene signature encoding molecules associated with antigen presentation and interferon-gamma signaling. Mice conditionally lacking CTLA-4 in thymic epithelial cells had no major immunological deficiencies but displayed a mildly increased inflammatory tone and a partial defect in the generation of Foxp3CD4 regulatory T cells. Consequently, these mice developed modest levels of autoantibodies and lymphocytic infiltration of peripheral tissues. Thus, CTLA-4 expression in mTECs complements Aire to establish T cell central tolerance.
髓质胸腺上皮细胞（mTECs）对于建立 T 细胞中枢耐受至关重要。转录因子 Aire 在这个过程中起着关键作用，但其他因素仍未得到充分研究。我们发现一小部分 mTEC 表达抑制性受体细胞毒性 T 淋巴细胞相关蛋白 4（CTLA-4）。这些 CTLA-4 细胞可在围产期检测到，在青年期达到峰值，并在缺乏 Aire 的情况下扩增六倍。单细胞转录组学揭示 CTLA-4 mTEC 表达一种独特的基因特征，编码与抗原呈递和干扰素-γ信号相关的分子。在胸腺上皮细胞中条件性缺乏 CTLA-4 的小鼠没有主要的免疫缺陷，但表现出炎症反应略有增加，Foxp3CD4 调节性 T 细胞的生成部分缺陷。因此，这些小鼠产生了适度水平的自身抗体和外周组织的淋巴细胞浸润。因此，CTLA-4 在 mTECs 中的表达补充了 Aire 以建立 T 细胞中枢耐受。
