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Nat Immunol

Memory CD4(+) T cells are generated in the human fetal intestine

Na Li, Vincent van Unen, Tamim Abdelaal, Nannan Guo, Sofya Kasatskaya, Kristin Ladell, James McLaren, Evgeniy Egorov, Mark Izraelson, Susana M. Chuva de Sousa Lopes, Thomas Höllt, Olga Britanova, Jeroen Eggermont, Noel de Miranda, Dmitriy Chudakov, David Price, Boudewijn P. F. Lelieveldt, and Frits Koning

Three kinetic modules of pseudotime-dependent genes (n= 1,376) depicted in a log-variance-stabilized expression heat map, indicating gene-enriched biological processes. Genes confirmed by mass cytometry and flow cytometry are denoted by black labels, and genes involved in TCR signaling are denoted by gray labels. The dashed gray box indicates the coordinated expression profile of TNF, FASL and FYN. Euclidean distance values comparing gene expression profiles for each ordered pair of neighboring cells along the pseudotime trajectory are shown in the graph (right).

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The fetus is thought to be protected from exposure to foreign antigens, yet CD45RO+ T cells reside in the fetal intestine. Here we combined functional assays with mass cytometry, single-cell RNA-sequencing and high-throughput T cell antigen receptor (TCR) sequencing to characterize the CD4+ T cell compartment in the human fetal intestine. We identified 22 CD4+ T cell clusters, including naive-like, regulatory-like and memory-like subpopulations, which were confirmed and further characterized at the transcriptional level. Memory-like CD4+ T cells had high expression of Ki-67, indicative of cell division, and CD5, a surrogate marker of TCR avidity, and produced the cytokines IFN-γ and IL-2. Pathway analysis revealed a differentiation trajectory associated with cellular activation and proinflammatory effector functions, and TCR repertoire analysis indicated clonal expansions, distinct repertoire characteristics and interconnections between subpopulations of memory-like CD4+ T cells. Imaging-mass cytometry indicated that memory-like CD4+ T cells colocalized with antigen-presenting cells. Collectively, these results provide evidence for the generation of memory-like CD4+ T cells in the human fetal intestine that is consistent with exposure to foreign antigens.

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Na Li, Vincent van Unen, Tamim Abdelaal, Nannan Guo, Sofya Kasatskaya, Kristin Ladell, James McLaren, et al., Memory CD4(+) T cells are generated in the human fetal intestine, Nat Immunol, 20, pp. 301–312, 2019.

BibTex 

@article{bib:li:2019,
    author       = { Li, Na and van Unen, Vincent and Abdelaal, Tamim and Guo, Nannan and Kasatskaya, Sofya and Ladell, Kristin and McLaren, James and Egorov, Evgeniy and Izraelson, Mark and Chuva de Sousa Lopes, Susana M. and Höllt, Thomas and Britanova, Olga and Eggermont, Jeroen and de Miranda, Noel and Chudakov, Dmitriy and Price, David and Lelieveldt, Boudewijn P. F. and Koning, Frits },    
    title        = { Memory CD4(+) T cells are generated in the human fetal intestine },
    journal      = { Nat Immunol },
    volume       = { 20 },
    year         = { 2019 },
    pages        = { 301--312 },
    doi          = { 10.1038/s41590-018-0294-9 },
    pubmedid     = { 30664737 },
    url          = { https://publications.graphics.tudelft.nl/papers/133 },
}