Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
J Exp Med. 2021 Feb 1;218(2). doi: 10.1084/jem.20192191.
The identification and characterization of rare immune cell populations in humans can be facilitated by their growth advantage in the context of specific genetic diseases. Here, we use autoimmune lymphoproliferative syndrome to identify a population of FAS-controlled TCRαβ+ T cells. They include CD4+, CD8+, and double-negative T cells and can be defined by a CD38+CD45RA+T-BET- expression pattern. These unconventional T cells are present in healthy individuals, are generated before birth, are enriched in lymphoid tissue, and do not expand during acute viral infection. They are characterized by a unique molecular signature that is unambiguously different from other known T cell differentiation subsets and independent of CD4 or CD8 expression. Functionally, FAS-controlled T cells represent highly proliferative, noncytotoxic T cells with an IL-10 cytokine bias. Mechanistically, regulation of this physiological population is mediated by FAS and CTLA4 signaling, and its survival is enhanced by mTOR and STAT3 signals. Genetic alterations in these pathways result in expansion of FAS-controlled T cells, which can cause significant lymphoproliferative disease.
在特定遗传疾病的背景下，通过其生长优势，可以促进对人类稀有免疫细胞群体的鉴定和特征描述。在这里，我们利用自身免疫性淋巴增生综合征来鉴定出一种受 Fas 调控的 TCRαβ+T 细胞群体。它们包括 CD4+、CD8+和双阴性 T 细胞，可以通过 CD38+CD45RA+T-BET-的表达模式来定义。这些非常规 T 细胞存在于健康个体中，在出生前产生，在淋巴组织中富集，并且在急性病毒感染期间不会扩增。它们的特征是具有独特的分子特征，与其他已知的 T 细胞分化亚群明显不同，并且独立于 CD4 或 CD8 的表达。从功能上讲，受 Fas 调控的 T 细胞是具有高增殖能力的非细胞毒性 T 细胞，具有 IL-10 细胞因子偏向性。从机制上讲，这些生理群体的调节受 Fas 和 CTLA4 信号的介导，其生存能力通过 mTOR 和 STAT3 信号增强。这些途径中的遗传改变导致 Fas 调控的 T 细胞扩增，从而导致严重的淋巴增生性疾病。
