Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, United States.
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
Front Immunol. 2023 Mar 28;14:1100490. doi: 10.3389/fimmu.2023.1100490. eCollection 2023.
Tuberculosis (TB) caused by (Mtb) infection is a serious threat to human health. Vaccination with BCG prevents the development of the most severe forms of TB disease in infants and was recently shown to prevent Mtb infection in previously uninfected adolescents. γδ T cells play a major role in host defense at mucosal sites and are known to respond robustly to mycobacterial infection. However, our understanding of the effects of BCG vaccination on γδ T cell responses is incomplete.
In this study we performed γδ T cell receptor (TCR) repertoire sequencing of samples provided pre- and post-BCG vaccination from 10 individuals to identify specific receptors and TCR clones that are induced by BCG.
Overall, there was no change in the diversity of γTCR or δTCR clonotypes in post- vs pre-BCG samples. Furthermore, the frequencies of TCR variable and joining region genes were minimally modulated by BCG vaccination at either the γTCR or δTCR loci. However, the γTCR and δTCR repertoires of individuals were highly dynamic; a median of ~1% of γTCR and ~6% of δTCR in the repertoire were found to significantly expand or contract in post- vs pre-BCG comparisons (FDR-q < 0.05). While many of the clonotypes whose frequency changed after BCG vaccination were not shared among multiple individuals in the cohort, several shared (i.e., "public") clonotypes were identified with a consistent increase or decrease in frequency across more than one individual; the degree of sharing of these clonotypes was significantly greater than the minimal sharing that would be expected among γTCR and δTCR repertoires. An analysis of Mtb antigen-reactive γδ T cells identified clonotypes that were similar or identical to the single-chain γTCRs and δTCRs that changed consistently after BCG vaccination; pairings of γTCRs and δTCRs that increased after BCG vaccination were significantly over-represented among the Mtb-reactive γδ T cells (p = 1.2e-6).
These findings generate hypotheses about specific γδTCR clonotypes that may expand in response to BCG vaccination and may recognize Mtb antigens. Future studies are required to validate and characterize these clonotypes, with an aim to better understand the role of γδ T cells in Mtb immunity.
由 （Mtb）感染引起的结核病（TB）对人类健康构成严重威胁。BCG 疫苗接种可预防婴儿最严重形式的结核病疾病，并最近被证明可预防先前未感染的青少年感染 Mtb。γδ T 细胞在粘膜部位的宿主防御中起主要作用，并且已知对分枝杆菌感染有强烈反应。然而，我们对 BCG 疫苗接种对 γδ T 细胞反应的影响的理解并不完整。
在这项研究中，我们对 10 名个体提供的接种 BCG 前后的样本进行了 γδ T 细胞受体（TCR）库测序，以鉴定由 BCG 诱导的特定受体和 TCR 克隆。
总体而言，BCG 后与 BCG 前样本的 γTCR 或 δTCR 克隆型多样性没有变化。此外，BCG 疫苗接种在 γTCR 或 δTCR 基因座上对 TCR 可变和连接区基因的频率仅有最小的调节。然而，个体的 γTCR 和 δTCR 库非常动态；在 BCG 后与 BCG 前的比较中，库中约有 1%的 γTCR 和 6%的 δTCR 发现显著扩增或收缩（FDR-q<0.05）。虽然 BCG 疫苗接种后频率发生变化的许多克隆型在队列中的多个个体中并不共享，但鉴定到了一些共享（即“公共”）克隆型，其频率在多个个体中一致增加或减少；这些克隆型的共享程度明显大于 γTCR 和 δTCR 库之间预期的最小共享程度。对 Mtb 抗原反应性 γδ T 细胞的分析鉴定了与 BCG 疫苗接种后一致变化的单链 γTCR 和 δTCR 相似或相同的克隆型；BCG 接种后增加的 γTCR 和 δTCR 配对在 Mtb 反应性 γδ T 细胞中显著过表达（p=1.2e-6）。
这些发现提出了关于可能对 BCG 疫苗接种有反应并可能识别 Mtb 抗原的特定 γδTCR 克隆型的假设。需要进一步的研究来验证和表征这些克隆型，目的是更好地了解 γδ T 细胞在 Mtb 免疫中的作用。
