Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Biology, St. Louis University, St. Louis, MO, USA.
Nat Immunol. 2020 Nov;21(11):1384-1396. doi: 10.1038/s41590-020-0781-7. Epub 2020 Sep 28.
T follicular helper (T) cells are critical in adaptive immune responses to pathogens and vaccines; however, what drives the initiation of their developmental program remains unclear. Studies suggest that a T cell antigen receptor (TCR)-dependent mechanism may be responsible for the earliest T cell-fate decision, but a critical aspect of the TCR has been overlooked: tonic TCR signaling. We hypothesized that tonic signaling influences early T cell development. Here, two murine TCR-transgenic CD4 T cells, LLO56 and LLO118, which recognize the same antigenic peptide presented on major histocompatibility complex molecules but experience disparate strengths of tonic signaling, revealed low tonic signaling promotes T cell differentiation. Polyclonal T cells paralleled these findings, with naive Nur77 expression distinguishing T cell potential. Two mouse lines were also generated to both increase and decrease tonic signaling strength, directly establishing an inverse relationship between tonic signaling strength and T cell development. Our findings elucidate a central role for tonic TCR signaling in early T cell-lineage decisions.
T 滤泡辅助 (T) 细胞在病原体和疫苗的适应性免疫反应中至关重要；然而，驱动其发育程序启动的原因仍不清楚。研究表明，T 细胞抗原受体 (TCR) 依赖性机制可能负责最早的 T 细胞命运决定，但 TCR 的一个关键方面被忽视了：TCR 的持续信号。我们假设持续信号会影响早期 T 细胞的发育。在这里，两种小鼠 TCR 转基因 CD4 T 细胞，LLO56 和 LLO118，它们识别主要组织相容性复合体分子上呈现的相同抗原肽，但经历不同强度的持续信号，揭示了低持续信号促进 T 细胞分化。多克隆 T 细胞与这些发现平行，幼稚 Nur77 表达区分 T 细胞潜能。还生成了两种小鼠品系，以增加和减少持续信号强度，直接建立了持续信号强度与 T 细胞发育之间的反比关系。我们的发现阐明了持续 TCR 信号在早期 T 细胞谱系决定中的核心作用。
