Fischer Sebastian, Stanke Frauke, Tümmler Burkhard
Clinic for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.
Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Hannover Medical School, Hannover, Germany.
Front Immunol. 2021 Feb 23;12:599133. doi: 10.3389/fimmu.2021.599133. eCollection 2021.
Sixteen monozygotic cystic fibrosis (CF) twin pairs of whom 14 pairs were homozygous for the most common p.Phe508del mutation were selected from the European Cystic Fibrosis Twin and Sibling Study Cohort. The monozygotic twins were examined in their T cell receptor (TCR) repertoire in peripheral blood by amplicon sequencing of the CDR3 variable region of the ß-chain. The recruitment of TCR J and V genes for recombination and selection in the thymus showed a strong genetic influence in the CF twin cohort as indicated by the shortest Jensen-Shannon distance to the twin individual. Exceptions were the clinically most discordant and/or most severely affected twin pairs where clonal expansion probably caused by recurrent pulmonary infections overshadowed the impact of the identical genomic blueprint. In general the Simpson clonality was low indicating that the population of TCRß clonotypes of the CF twins was dominated by the naïve T-cell repertoire. Intrapair sharing of clonotypes was significantly more frequent among monozygotic CF twins than among pairs of unrelated CF patients. Complete nucleotide sequence identity was observed in about 0.11% of CDR3 sequences which partially should represent persisting fetal clones derived from the same progenitor T cells. Complete amino acid sequence identity was noted in 0.59% of clonotypes. Of the nearly 40,000 frequent amino acid clonotypes shared by at least two twin siblings 99.8% were already known within the immuneACCESS database and only 73 had yet not been detected indicating that the CDR3ß repertoire of CF children and adolescents does not carry a disease-specific signature but rather shares public clones with that of the non-CF community. Clonotypes shared within twin pairs and between unrelated CF siblings were highly abundant among healthy non-CF people, less represented in individuals with infectious disease and uncommon in patients with cancer. This subset of shared CF clonotypes defines CDR3 amino acid sequences that are more common in health than in disease.
从欧洲囊性纤维化双胞胎和兄弟姐妹研究队列中选取了16对单卵双胞胎，其中14对对于最常见的p.Phe508del突变是纯合的。通过对β链CDR3可变区进行扩增子测序，对外周血中的单卵双胞胎的T细胞受体（TCR）库进行了检测。TCR J和V基因在胸腺中的重组和选择招募显示出对囊性纤维化双胞胎队列有很强的遗传影响，这一点通过与双胞胎个体的最短詹森-香农距离得以表明。例外情况是临床上最不一致和/或受影响最严重的双胞胎对，其中可能由反复肺部感染导致的克隆性扩增掩盖了相同基因组蓝图的影响。总体而言，辛普森克隆性较低，表明囊性纤维化双胞胎的TCRβ克隆型群体以幼稚T细胞库为主。单卵囊性纤维化双胞胎中克隆型的配对内共享比不相关的囊性纤维化患者对中更为频繁。在约0.11%的CDR3序列中观察到完全核苷酸序列同一性，这部分应代表源自相同祖细胞T细胞的持续胎儿克隆。在0.59%的克隆型中注意到完全氨基酸序列同一性。在至少两个双胞胎兄弟姐妹共有的近40,000种常见氨基酸克隆型中，99.8%在immuneACCESS数据库中已经为人所知，只有73种尚未被检测到，这表明囊性纤维化儿童和青少年的CDR3β库没有携带疾病特异性特征，而是与非囊性纤维化群体共享公共克隆。在双胞胎对之间以及不相关的囊性纤维化兄弟姐妹之间共享的克隆型在健康的非囊性纤维化人群中高度丰富，在传染病患者中较少，在癌症患者中罕见。这种共享的囊性纤维化克隆型子集定义了在健康状态下比疾病状态下更常见的CDR3氨基酸序列。
