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

doi:10.1111/ajt.16970

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

Department of Pharmacy

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

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 language	English
Pages (from-to)	1329-1338
Number of pages	10
Journal	American Journal of Transplantation
Volume	22
Issue number	5
DOIs	https://doi.org/10.1111/ajt.16970
Publication status	Published - 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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10.1111/ajt.16970

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Lema, D. A., Jankowska-Gan, E., Nair, A., Kanaan, S. B., Little, C. J., Foley, D. P., Raza Naqvi, A., Wang, J., Hong, S., Nelson, J. L., Al-Adra, D., Burlingham, W. J., & Sullivan, J. A. (2022). 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. American Journal of Transplantation, 22(5), 1329-1338. https://doi.org/10.1111/ajt.16970

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title = "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",

abstract = "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.",

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

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 Villal{\'o}n 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: {\textcopyright} 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.",

year = "2022",

month = may,

doi = "10.1111/ajt.16970",

language = "English",

volume = "22",

pages = "1329--1338",

journal = "American Journal of Transplantation",

issn = "1600-6135",

publisher = "Wiley-Blackwell",

number = "5",

}

Lema, DA, Jankowska-Gan, E, Nair, A, Kanaan, SB, Little, CJ, Foley, DP, Raza Naqvi, A, Wang, J, Hong, S, Nelson, JL, Al-Adra, D, Burlingham, WJ & Sullivan, JA 2022, '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', American Journal of Transplantation, vol. 22, no. 5, pp. 1329-1338. https://doi.org/10.1111/ajt.16970

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. / Lema, Diego A.; Jankowska-Gan, Ewa; Nair, Ashita et al.

In: American Journal of Transplantation, Vol. 22, No. 5, 05.2022, p. 1329-1338.

Research output: Contribution to journal › Article › peer-review

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T1 - Cross-decoration of dendritic cells by non-inherited maternal antigen-containing extracellular vesicles

T2 - Potential mechanism for PD-L1-based tolerance in cord blood and organ transplantation

AU - Lema, Diego A.

AU - Jankowska-Gan, Ewa

AU - Nair, Ashita

AU - Kanaan, Sami B.

AU - Little, Christopher J.

AU - Foley, David P.

AU - Raza Naqvi, Afsar

AU - Wang, Jianxin

AU - Hong, Seungpyo

AU - Nelson, J. Lee

AU - Al-Adra, David

AU - Burlingham, William J.

AU - Sullivan, Jeremy A.

N1 - 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.

PY - 2022/5

Y1 - 2022/5

N2 - 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.

AB - 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.

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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

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