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

Nat Immunol. 2019 Mar;20(3):301-312. doi: 10.1038/s41590-018-0294-9. Epub 2019 Jan 21.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen-Presenting Cells / cytology
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD5 Antigens / genetics
  • CD5 Antigens / immunology
  • CD5 Antigens / metabolism
  • Cells, Cultured
  • Fetus / cytology
  • Fetus / immunology*
  • Fetus / metabolism
  • Flow Cytometry
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Developmental / immunology
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunologic Memory / genetics
  • Immunologic Memory / immunology*
  • Immunophenotyping
  • Intestines / cytology
  • Intestines / embryology
  • Intestines / immunology*
  • Ki-67 Antigen / genetics
  • Ki-67 Antigen / immunology
  • Ki-67 Antigen / metabolism

Substances

  • CD5 Antigens
  • Ki-67 Antigen