Human Tregs at the materno-fetal interface show site-specific adaptation reminiscent of tumor Tregs
Judith Wienke, Laura Brouwers, Leone M. van der Burg, Michal Mokry, Rianne C. Scholman, Peter G.J. Nikkels, Bas B. van Rijn, Femke van Wijk
Judith Wienke, Laura Brouwers, Leone M. van der Burg, Michal Mokry, Rianne C. Scholman, Peter G.J. Nikkels, Bas B. van Rijn, Femke van Wijk
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Research Article Immunology Reproductive biology

Human Tregs at the materno-fetal interface show site-specific adaptation reminiscent of tumor Tregs

Abstract

Tregs are crucial for maintaining maternal immunotolerance against the semiallogeneic fetus. We investigated the elusive transcriptional profile and functional adaptation of human uterine Tregs (uTregs) during pregnancy. Uterine biopsies, from placental bed (materno-fetal interface) and incision site (control) and blood were obtained from women with uncomplicated pregnancies undergoing cesarean section. Tregs and CD4+ non-Tregs were isolated for transcriptomic profiling by Cel-Seq2. Results were validated on protein and single cell levels by flow cytometry. Placental bed uTregs showed elevated expression of Treg signature markers, including FOXP3, CTLA-4, and TIGIT. Their transcriptional profile was indicative of late-stage effector Treg differentiation and chronic activation, with increased expression of immune checkpoints GITR, TNFR2, OX-40, and 4-1BB; genes associated with suppressive capacity (HAVCR2, IL10, LAYN, and PDCD1); and transcription factors MAF, PRDM1, BATF, and VDR. uTregs mirrored non-Treg Th1 polarization and tissue residency. The particular transcriptional signature of placental bed uTregs overlapped strongly with that of tumor-infiltrating Tregs and was remarkably pronounced at the placental bed compared with uterine control site. In conclusion, human uTregs acquire a differentiated effector Treg profile similar to tumor-infiltrating Tregs, specifically at the materno-fetal interface. This introduces the concept of site-specific transcriptional adaptation of Tregs within 1 organ.

Authors

Judith Wienke, Laura Brouwers, Leone M. van der Burg, Michal Mokry, Rianne C. Scholman, Peter G.J. Nikkels, Bas B. van Rijn, Femke van Wijk

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Figure 6

uTregs share their transcriptional signature with tissue- and tumor-infiltrating Tregs.

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uTregs share their transcriptional signature with tissue- and tumor-infi...
(A) GSEA with a published murine PAN-tissue gene signature (18), comparing uTregs and bTregs. NES, normalized enrichment score; FDR, FDR adjusted P value. (B) Venn diagram showing the numbers of genes upregulated in uTregs compared with bTregs (Padj < 0.05) (and genes in the uTreg core signature in parentheses), which are represented in tissue-specific and tissue-shared published murine gene signatures (18). VAT, visceral adipose tissue. (C) Heatmap showing the expression of the 59 genes that were part of the murine PAN-tissue signature and upregulated in uTregs compared with bTregs (Padj < 0.05) (18). Expression values were mean centered and scaled per gene. (D) The number of genes shared between the uTreg core signature and published human TITR signatures or healthy tissue Treg signatures (14, 17, 25, 95–100). Numbers behind bars indicate the number of shared genes out of the total number of genes in the specific signature. (E) The genes that were most often shared between the uTreg core signature and human TITR signatures (shared in ≥ 4 of 7 signatures). (F) The genes that were most often shared between the uTreg core signature and human healthy tissue Treg signatures (shared in ≥ 2 of 3 signatures).