Staphylococcus aureus convert neonatal conventional CD4(+) T cells into FOXP3(+) CD25(+) CD127(low) T cells via the PD-1/PD-L1 axis.
The gut microbiota provides an important stimulus for the induction of regulatory T (Treg) cells in mice, whether this applies to newborn children is unknown. In Swedish children, Staphylococcus aureus has become a common early colonizer of the gut. Here, we sought to study the effects of bacterial stimulation on neonatal CD4(+) T cells for the induction of CD25(+) CD127(low) Treg cells in vitro. The proportion of circulating CD25(+) CD127(low) Treg cells and their expression of FOXP3, Helios and CTLA-4 was examined in newborns and adults. To evaluate if commensal gut bacteria could induce Treg cells, CellTrace violet-stained non-Treg cells from cord or peripheral blood from adults were co-cultured with autologous CD25(+) CD127(low) Treg cells and remaining mononuclear cells and stimulated with S. aureus. Newborns had a significantly lower proportion of CD25(+) CD127(low) Treg cells than adults, but these cells were Helios(+) and CTLA-4(+) to a higher extent than in adults. FOXP3(+) CD25(+) CD127(low) T cells were induced mainly in neonatal CellTrace-stained non-Treg cells after stimulation with S. aureus. In cell cultures from adults, S. aureus induced CD25(+) CD127(low) T cells only if sorted naive CD45RA(+) non-Treg cells were used, but these cells expressed less FOXP3 than those induced from newborns. Sorted neonatal CD25(+) CD127(low) T cells from S. aureus-stimulated cultures were still suppressive. Finally, blocking PD-L1 during stimulation reduced the induction of FOXP3(+) CD25(+) CD127(low) T cells. These results suggest that newborns have a higher proportion of circulating thymically derived Helios(+) Treg cells than adults and that S. aureus possess an ability to convert neonatal conventional CD4(+) T cells into FOXP3(+) CD25(+) CD127(low) Treg cells via the PD-1/PD-L1 axis.
Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Hardis
H
Rabe
Inger
I
Nordström
Kerstin
K
Andersson
Anna-Carin
AC
Lundell
Anna
A
Rudin
D000328:Adult; D000367:Age Factors; D060890:B7-H1 Antigen / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D060908:CTLA-4 Antigen / Q000378:metabolism; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000378:metabolism; D007231:Infant, Newborn; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D015398:Signal Transduction; D013203:Staphylococcal Infections / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology
D060890:B7-H1 Antigen; D015415:Biomarkers; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C111431:IKZF2 protein, human; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D053699:Interleukin-7 Receptor alpha Subunit; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D051740:Ikaros Transcription Factor; D017493:Leukocyte Common Antigens
FOXP3+ regulatory T cells; Helios; Staphylococcus aureus; cord blood; programmed cell death 1