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

• Published in: Nature immunology Vol. 20; no. 3; pp. 301 - 312
• Main Authors: Li, Na, van Unen, Vincent, Abdelaal, Tamim, Guo, Nannan, Kasatskaya, Sofya A., Ladell, Kristin, McLaren, James E., Egorov, Evgeny S., Izraelson, Mark, Chuva de Sousa Lopes, Susana M., Höllt, Thomas, Britanova, Olga V, Eggermont, Jeroen, de Miranda, Noel F. C. C., Chudakov, Dmitriy M., Price, David A., Lelieveldt, Boudewijn P. F., Koning, Frits
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2019; Nature Publishing Group
• Subjects: 631/250/1619; 631/250/2152; 631/250/347; Antigen-presenting cells; Antigen-Presenting Cells - cytology; Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - metabolism; Antigens; Avidity; Biomedical and Life Sciences; Biomedicine; CD4 antigen; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD5 antigen; CD5 Antigens - genetics; CD5 Antigens - immunology; CD5 Antigens - metabolism; Cell division; Cells, Cultured; Cytometry; Fetus - cytology; Fetus - immunology; Fetus - metabolism; Fetuses; Flow Cytometry; Gene Expression Profiling - methods; Gene Expression Regulation, Developmental - immunology; High-Throughput Nucleotide Sequencing; Humans; Immunologic Memory - genetics; Immunologic Memory - immunology; Immunological memory; Immunology; Immunophenotyping; Infectious Diseases; Inflammation; Interleukin 2; Intestine; Intestines - cytology; Intestines - embryology; Intestines - immunology; Ki-67 Antigen - genetics; Ki-67 Antigen - immunology; Ki-67 Antigen - metabolism; Lymphocytes; Lymphocytes T; Memory cells; Ribonucleic acid; RNA; Subpopulations; T cell receptors; Transcription; γ-Interferon
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-018-0294-9

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. Koning and colleagues used mass cytometry, single-cell RNA-seq and high-throughput TCR sequencing to characterize the CD4 + T cell compartment in the human fetal intestine.