Themis sets the signal threshold for positive and negative selection in T-cell development.
Themis sets the signal threshold for positive and negative selection in T-cell development.
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发展一种自我耐受的T细胞受体(TCR)谱系，具有识别感染性病原体的能力，取决于对TCR信号的适当调节。在胸腺T细胞发育过程中，由于准随机产生的TCR与主要组织相容性复合体(MHC)蛋白呈现的自体多肽相互作用，TCR的功能被削减。与自身MHC蛋白的低亲和力TCR相互作用产生的微弱信号启动了“阳性选择”，导致表达CD_4或CD_8αβ的“单阳性”胸腺细胞从CD_4+CD_8αβ+“双阳性”前体成熟。这些细胞发育成次级淋巴器官的成熟幼稚T细胞。TCR与高亲和力激动剂自身配体的相互作用通过激活诱导功能分化的自身抗原经历的T细胞的凋亡或激动剂选择而导致“负选择”。在这里，我们表明，阳性选择是由于T细胞特异性蛋白Themis，，，能够通过SHP1的募集和激活来特异性地减弱TCR信号强度，以响应低亲和力但不是高亲和力的TCR参与。THEMIS充当模数转换器，将分级的TCR亲和力转换为明确的选择结果。通过抑制温和的TCR信号，Themis提高了激活的亲和力阈值，使具有幼稚表型的T细胞能够对低亲和力自身抗原做出积极选择。
Development of a self-tolerant T-cell receptor (TCR) repertoire with the potential to recognize the universe of infectious agents depends on proper regulation of TCR signalling. The repertoire is whittled down during T-cell development in the thymus by the ability of quasi-randomly generated TCRs to interact with self-peptides presented by major histocompatibility complex (MHC) proteins. Low-affinity TCR interactions with self-MHC proteins generate weak signals that initiate ‘positive selection’, causing maturation of CD4- or CD8αβ-expressing ‘single-positive’ thymocytes from CD4+CD8αβ+‘double-positive’ precursors. These develop into mature naive T cells of the secondary lymphoid organs. TCR interaction with high-affinity agonist self-ligands results in ‘negative selection’ by activation-induced apoptosis or ‘agonist selection’ of functionally differentiated self-antigen-experienced T cells,. Here we show that positive selection is enabled by the ability of the T-cell-specific protein Themis,,,,,to specifically attenuate TCR signal strength via SHP1 recruitment and activation in response to low- but not high-affinity TCR engagement. Themis acts as an analog-to-digital converter translating graded TCR affinity into clear-cut selection outcome. By dampening mild TCR signals Themis increases the affinity threshold for activation, enabling positive selection of T cells with a naive phenotype in response to low-affinity self-antigens.