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

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.

‘Layered immunity’ and the ‘neonatal window of opportunity’ – timed succession of non‐redundant phases to establish mucosal host–microbial homeostasis after birth

“…The underlying reasons are incompletely understood but breast‐milk‐derived maternal immunoglobulin and neonatal Treg cells were identified to contribute to the active suppression of T‐cell maturation before weaning . In humans, T‐cell homing to the intestine already occurs in the fetus . Yet fetal and adult T cells derive from hematopoietic stem cells that originate in different tissues (i.e.…”

“…Interestingly, in contrast to the mouse, host effector lymphocytes are detected in the human intestine early during gestation. It is not clear, whether it is self‐antigen that stimulates this effector response and how (self) tolerance is maintained at this developmental stage . Finally, the layered development of the immune system is evolutionarily driven and follows a cost–benefit principle.…”

“…It is not clear, whether it is selfantigen that stimulates this effector response and how (self) tolerance is maintained at this developmental stage. 90 Finally, the layered development of the immune system is evolutionarily driven and follows a cost-benefit principle. The maintenance of an elaborate immune system may come at a price and may have to be adapted to the availability of energy resources that at this time-point might rather be dedicated to growth and development.…”

“…60,62 In humans, T-cell homing to the intestine already occurs in the fetus. 90,91 Yet fetal and adult T cells derive from hematopoietic stem cells that originate in different tissues (i.e. fetal liver versus adult bone marrow) and have distinct properties: Fetally derived cells exhibit higher proliferative capacity and are more prone to a tolerogenic response.…”

Influence of maternal microbiota during pregnancy on infant immunity

“…For example, memory CD4 + and CD8 + T cells can be identified towards the end of the first trimester in human fetal gut [79]. Memory CD4 T cells in fetal intestines have been shown to co-localize with APCs and produce IFN-γ, IL-2 or tumor necrosis factor (TNF)-α, promoting intestinal development [80,81]. Altogether, these suggest that early fetal exposure to microbial antigens may impact immunity.…”