Cross-decoration of dendritic cells by non-inherited maternal antigen-containing extracellular vesicles: Potential mechanism for PD-L1-based tolerance in cord blood and organ transplantation

Diego A. Lema, Ewa Jankowska-Gan, Ashita Nair, Sami B. Kanaan, Christopher J. Little, David P. Foley, Afsar Raza Naqvi, Jianxin Wang, Seungpyo Hong, J. Lee Nelson, David Al-Adra, William J. Burlingham, Jeremy A. Sullivan

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


Exposure to non-inherited maternal antigens (NIMA) during the fetal period induces lifelong split tolerance to grafts expressing these allo-antigens. In adult mice, the production of extracellular vesicles (EVs) from maternal microchimeric cells causes cross-decoration (XD) of offspring dendritic cells (DC) with NIMA and upregulation of PD-L1, contributing to NIMA tolerance. To see how this may apply to humans, we tested NIMA acquisition by fetal DCS in human cord blood. The average percentage of NIMA-XD among total DCs was 2.6% for myeloid and 4.5% for Plasmacytoid DC. These cells showed higher PD-L1 expression than their non-XD counterparts (mDC: p =.0016; pDC: p =.024). We detected CD9+ EVs bearing NIMA and PD-L1 in cord blood. To determine if this immune regulatory mechanism persists beyond the pregnancy, we analyzed NIMA-expressing kidney and liver transplant recipients. We found donor antigen XD DCs in peripheral blood and graft-infiltrating DCs. As in cord blood, the pattern of donor antigen expression was punctate, and PD-L1 expression was upregulated, likely due to both protein and miRNA acquired from EV. Our findings support a mechanism for split tolerance to NIMAs that develops during pregnancy and is recapitulated in adult transplant recipients.

Original languageEnglish
Pages (from-to)1329-1338
Number of pages10
JournalAmerican Journal of Transplantation
Issue number5
Publication statusPublished - 2022 May

Bibliographical note

Funding Information:
We would like to express our gratitude to the mothers, patients, and their family members that have selflessly contributed to this study. Likewise, we wish to acknowledge the invaluable help of the staff of University of Wisconsin Hospital, Meriter Hospital and Fred Hutchinson in collecting these samples, especially Dr. Rosalina Villalón Landeros, Robin Wasielewski, and Judy Allen. We would also like to thank Mr. John Fechner for his technical assistance with HLA‐related flow cytometry. This work was supported by the following grants: NIH1R21A147157‐01, NIH R01 144AAA9541, NIH R03 AI159288, NIH R01 HL117737, and University of Wisconsin Carbone Cancer Center Support Grant P30 CA014520. SBK and JLN are co‐founders of Chimerocyte, Inc., which develops highly sensitive chimerism analysis technologies. Chimerocyte, Inc. had no role in funding this research project.

Publisher Copyright:
© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)


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