Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary.
Szeged Scientists Academy, 6720 Szeged, Hungary.
Proc Natl Acad Sci U S A. 2021 Sep 14;118(37). doi: 10.1073/pnas.2100542118.
Adaptive immune recognition is mediated by the binding of peptide-human leukocyte antigen complexes by T cells. Positive selection of T cells in the thymus is a fundamental step in the generation of a responding T cell repertoire: only those T cells survive that recognize human peptides presented on the surface of cortical thymic epithelial cells. We propose that while this step is essential for optimal immune function, the process results in a defective T cell repertoire because it is mediated by self-peptides. To test our hypothesis, we focused on amino acid motifs of peptides in contact with T cell receptors. We found that motifs rarely or not found in the human proteome are unlikely to be recognized by the immune system just like the ones that are not expressed in cortical thymic epithelial cells or not presented on their surface. Peptides carrying such motifs were especially dissimilar to human proteins. Importantly, we present our main findings on two independent T cell activation datasets and directly demonstrate the absence of naïve T cells in the repertoire of healthy individuals. We also show that T cell cross-reactivity is unable to compensate for the absence of positively selected T cells. Additionally, we show that the proposed mechanism could influence the risk for different infectious diseases. In sum, our results suggest a side effect of T cell positive selection, which could explain the nonresponsiveness to many nonself peptides and could improve the understanding of adaptive immune recognition.
适应性免疫识别是由 T 细胞结合肽-人类白细胞抗原复合物介导的。T 细胞在胸腺中的阳性选择是产生应答性 T 细胞库的基本步骤：只有那些识别皮质胸腺上皮细胞表面呈现的人类肽的 T 细胞才能存活。我们提出，虽然这一步对于最佳免疫功能至关重要，但该过程导致了有缺陷的 T 细胞库，因为它是由自身肽介导的。为了检验我们的假设，我们专注于与 T 细胞受体接触的肽的氨基酸基序。我们发现，在人类蛋白质组中很少或没有发现的基序，就像那些在皮质胸腺上皮细胞中不表达或不在其表面呈现的基序一样，不太可能被免疫系统识别。携带这种基序的肽与人类蛋白尤其不同。重要的是，我们在两个独立的 T 细胞激活数据集上展示了我们的主要发现，并直接证明了健康个体的库中不存在幼稚 T 细胞。我们还表明，T 细胞交叉反应不能弥补阳性选择 T 细胞的缺失。此外，我们还表明，所提出的机制可能会影响不同传染病的风险。总之，我们的结果表明 T 细胞阳性选择的一种副作用，这可以解释对许多非自身肽的无反应性，并有助于更好地理解适应性免疫识别。
