Microbial exposure drives polyclonal expansion of innate γδ 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 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, we monitored the γ-chain (TRG) and δ-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 Vγ9 and Vδ2 chains with low junctional diversity and usage of non-TRDJ1 gene segments, reminiscent of early ontogenetic subsets of γδ T cells. Further profiling revealed that these innate, public Vγ9Vδ2+ T cells underwent an immediate TCR-driven polyclonal proliferation within the first 4 wk of life. In contrast, γδ T cells using Vδ1+ and Vδ3+TRD rearrangements did not significantly expand after birth. However, different environmental cues may lead to the observed increase of Vδ1+ and Vδ3+TRD sequences in the majority of African children. In summary, we show how dynamic γδ TCR repertoires develop directly after birth and present important differences among γδ T cell subsets.

Innate and adaptive γδ T cells: How, when, and why

“…These microbial cues may include phosphoantigen-producing commensal microbiota (38,118) which might be activating the neonatal Vγ9Vδ2 T cells in preparation for the host to rapidly mount immune responses upon pathogen encounter. The polyclonal response of Vγ9Vδ2 T cells to phosphoantigens goes in line with the innate character attributed to Vγ9Vδ2 T cells and intrathymic programming (see also section 5) (29,117,119). However, these cells still evolve in the periphery adapting on environmental signals they encounter (29,117).…”

“…Follow-up of infants γδ TCR repertoire showed a remarkable stability of the repertoire (117). In infants vaccinated or not at birth with the phosphoantigen-containing BCG vaccine, the Vγ9Vδ2 T cell repertoire and function did not differ at 10 weeks of age (29).…”

A fetal wave of human type-3 γδ T cells with restricted TCR diversity persists into adulthood

“…5a). This may have been a consequence of an expansion of public fetal-derived Vγ9Vδ2 T cell in the perinatal period 31,32 .…”

Diversity in recognition and function of human γδ T cells

“…The δ chain, on the other hand, exhibits considerable CDR3 sequence variability between and within individuals-public CDR3 sequences generally do not exceed 2% of total TRD sequences. 119 Interestingly, the δ chain shows a strong enrichment of hydrophobic amino acids at position 97 in the CDR3 of the Vδ2 chain, 120 a residue generated through N-nucleotide addition. Mutation of this residue and E28 of CDR1δ diminishes pAg reactivity.…”