MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Singapore Immunology Network, Agency of Science, Technology and Research, Singapore, Singapore.
Nat Immunol. 2018 Jul;19(7):742-754. doi: 10.1038/s41590-018-0133-z. Epub 2018 Jun 20.
To tackle the complexity of cross-reactive and pathogen-specific T cell responses against related Salmonella serovars, we used mass cytometry, unbiased single-cell cloning, live fluorescence barcoding, and T cell-receptor sequencing to reconstruct the Salmonella-specific repertoire of circulating effector CD4 T cells, isolated from volunteers challenged with Salmonella enterica serovar Typhi (S. Typhi) or Salmonella Paratyphi A (S. Paratyphi). We describe the expansion of cross-reactive responses against distantly related Salmonella serovars and of clonotypes recognizing immunodominant antigens uniquely expressed by S. Typhi or S. Paratyphi A. In addition, single-amino acid variations in two immunodominant proteins, CdtB and PhoN, lead to the accumulation of T cells that do not cross-react against the different serovars, thus demonstrating how minor sequence variations in a complex microorganism shape the pathogen-specific T cell repertoire. Our results identify immune-dominant, serovar-specific, and cross-reactive T cell antigens, which should aid in the design of T cell-vaccination strategies against Salmonella.
为了应对针对相关沙门氏菌血清型的交叉反应和病原体特异性 T 细胞反应的复杂性，我们使用了质谱流式细胞术、无偏单细胞克隆、活荧光条形码和 T 细胞受体测序，来重建来自志愿者的循环效应 CD4 T 细胞的沙门氏菌特异性库，这些志愿者受到伤寒沙门氏菌（S. Typhi）或副伤寒沙门氏菌 A（S. Paratyphi A）的挑战。我们描述了针对远缘相关沙门氏菌血清型的交叉反应性反应的扩展，以及针对伤寒沙门氏菌或副伤寒沙门氏菌 A 特有的免疫显性抗原的克隆型的识别。此外，两种免疫显性蛋白 CdtB 和 PhoN 中的单个氨基酸变异导致不针对不同血清型发生交叉反应的 T 细胞积累，从而证明了复杂微生物中的微小序列变异如何塑造病原体特异性 T 细胞库。我们的研究结果确定了免疫显性、血清型特异性和交叉反应性 T 细胞抗原，这应该有助于设计针对沙门氏菌的 T 细胞疫苗接种策略。
