Dataset Information

Microbial exposure drives polyclonal expansion of innate ?? T cells immediately after birth.

ABSTRACT: Starting at birth, the immune system of newborns and children encounters and is influenced by environmental challenges. It is still not completely understood how ?? T cells emerge and adapt during early life. Studying the composition of T cell receptors (TCRs) using next-generation sequencing (NGS) in neonates, infants, and children can provide valuable insights into the adaptation of T cell subsets. To investigate how neonatal ?? T cell repertoires are shaped by microbial exposure after birth, we monitored the ?-chain (TRG) and ?-chain (TRD) repertoires of peripheral blood T cells in newborns, infants, and young children from Europe and sub-Saharan Africa. We identified a set of TRG and TRD sequences that were shared by all children from Europe and Africa. These were primarily public clones, characterized by simple rearrangements of V?9 and V?2 chains with low junctional diversity and usage of non-TRDJ1 gene segments, reminiscent of early ontogenetic subsets of ?? T cells. Further profiling revealed that these innate, public V?9V?2⁺ T cells underwent an immediate TCR-driven polyclonal proliferation within the first 4 wk of life. In contrast, ?? T cells using V?1⁺ and V?3⁺ TRD rearrangements did not significantly expand after birth. However, different environmental cues may lead to the observed increase of V?1⁺ and V?3⁺ TRD sequences in the majority of African children. In summary, we show how dynamic ?? TCR repertoires develop directly after birth and present important differences among ?? T cell subsets.

SUBMITTER: Ravens S

PROVIDER: S-EPMC7414158 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Publications

Microbial exposure drives polyclonal expansion of innate γδ T cells immediately after birth.

Ravens Sarina S Fichtner Alina S AS Willers Maike M Torkornoo Dennis D Pirr Sabine S Schöning Jennifer J Deseke Malte M Sandrock Inga I Bubke Anja A Wilharm Anneke A Dodoo Daniel D Egyir Beverly B Flanagan Katie L KL Steinbrück Lars L Dickinson Paul P Ghazal Peter P Adu Bright B Viemann Dorothee D Prinz Immo I

Proceedings of the National Academy of Sciences of the United States of America 20200720 31

Starting at birth, the immune system of newborns and children encounters and is influenced by environmental challenges. It is still not completely understood how γδ T cells emerge and adapt during early life. Studying the composition of T cell receptors (TCRs) using next-generation sequencing (NGS) in neonates, infants, and children can provide valuable insights into the adaptation of T cell subsets. To investigate how neonatal γδ T cell repertoires are shaped by microbial exposure after birth, ...[more]

PMID: 32690687

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Project description:γδ T cells are important components of the immune system due to their ability to elicit a fast and strong response against infected and transformed cells. Because they can specifically and effectively kill target cells in an MHC independent fashion, there is great interest to utilize these cells in anti-tumor therapies where antigen presentation may be hampered. Since only a small fraction of T cells in the blood or tumor tissue are γδ T cells, they require extensive expansion to allow for fundamental, preclinical and ex vivo research. Although expansion protocols can be successful, most are based on depletion of other cell types rather than γδ T cell specific isolation, resulting in unpredictable purity of the isolated fraction. Moreover, the primary focus only lies with expansion of Vδ2+ T cells, while Vδ1+ T cells likewise have anti-tumor potential. Here, we investigated whether γδ T cells directly isolated from blood could be efficiently expanded while maintaining function. γδ T cell subsets were isolated using MACS separation, followed by FACS sorting, yielding >99% pure γδ T cells. Isolated Vδ1+ and Vδ2+ T cells could effectively expand immediately after isolation or upon freeze/thawing and reached expansion ratios between 200 to 2000-fold starting from varying numbers using cytokine supported feeder stimulations. MACS/FACS isolated and PHA stimulated γδ T cells expanded as good as immobilized antibody mediated stimulated cells in PBMCs, but delivered purer cells. After expansion, potential effector functions of γδ T cells were demonstrated by IFN-γ, TNF-α and granzyme B production upon PMA/ionomycin stimulation and effective killing capacity of multiple tumor cell lines was confirmed in killing assays. In conclusion, pure γδ T cells can productively be expanded while maintaining their anti-tumor effector functions against tumor cells. Moreover, γδ T cells could be expanded from low starting numbers suggesting that this protocol may even allow for expansion of cells extracted from tumor biopsies.

Dataset Information

Microbial exposure drives polyclonal expansion of innate ?? T cells immediately after birth.

Publications

Microbial exposure drives polyclonal expansion of innate γδ T cells immediately after birth.

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