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Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance.

Publication ,  Journal Article
Bracamonte-Baran, W; Florentin, J; Zhou, Y; Jankowska-Gan, E; Haynes, WJ; Zhong, W; Brennan, TV; Dutta, P; Claas, FHJ; van Rood, JJ; Burlingham, WJ
Published in: Proceedings of the National Academy of Sciences of the United States of America
January 2017

Maternal microchimerism (MMc) has been associated with development of allospecific transplant tolerance, antitumor immunity, and cross-generational reproductive fitness, but its mode of action is unknown. We found in a murine model that MMc caused exposure to the noninherited maternal antigens in all offspring, but in some, MMc magnitude was enough to cause membrane alloantigen acquisition (mAAQ; "cross-dressing") of host dendritic cells (DCs). Extracellular vesicle (EV)-enriched serum fractions from mAAQ+, but not from non-mAAQ, mice reproduced the DC cross-dressing phenomenon in vitro. In vivo, mAAQ was associated with increased expression of immune modulators PD-L1 (programmed death-ligand 1) and CD86 by myeloid DCs (mDCs) and decreased presentation of allopeptide+self-MHC complexes, along with increased PD-L1, on plasmacytoid DCs (pDCs). Remarkably, both serum EV-enriched fractions and membrane microdomains containing the acquired MHC alloantigens included CD86, but completely excluded PD-L1. In contrast, EV-enriched fractions and microdomains containing allopeptide+self-MHC did not exclude PD-L1. Adoptive transfer of allospecific transgenic CD4 T cells revealed a "split tolerance" status in mAAQ+ mice: T cells recognizing intact acquired MHC alloantigens proliferated, whereas those responding to allopeptide+self-MHC did not. Using isolated pDCs and mDCs for in vitro culture with allopeptide+self-MHC-specific CD4 T cells, we could replicate their normal activation in non-mAAQ mice, and PD-L1-dependent anergy in mAAQ+ hosts. We propose that EVs provide a physiologic link between microchimerism and split tolerance, with implications for tumor immunity, transplantation, autoimmunity, and reproductive success.

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Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

January 2017

Volume

114

Issue

5

Start / End Page

1099 / 1104

Related Subject Headings

  • T-Cell Antigen Receptor Specificity
  • Pregnancy
  • Models, Immunological
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Maternal-Fetal Exchange
  • Male
  • Isoantigens
  • Immune Tolerance
 

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Bracamonte-Baran, W., Florentin, J., Zhou, Y., Jankowska-Gan, E., Haynes, W. J., Zhong, W., … Burlingham, W. J. (2017). Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance. Proceedings of the National Academy of Sciences of the United States of America, 114(5), 1099–1104. https://doi.org/10.1073/pnas.1618364114
Bracamonte-Baran, William, Jonathan Florentin, Ying Zhou, Ewa Jankowska-Gan, W John Haynes, Weixiong Zhong, Todd V. Brennan, et al. “Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance.Proceedings of the National Academy of Sciences of the United States of America 114, no. 5 (January 2017): 1099–1104. https://doi.org/10.1073/pnas.1618364114.
Bracamonte-Baran W, Florentin J, Zhou Y, Jankowska-Gan E, Haynes WJ, Zhong W, et al. Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance. Proceedings of the National Academy of Sciences of the United States of America. 2017 Jan;114(5):1099–104.
Bracamonte-Baran, William, et al. “Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance.Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 5, Jan. 2017, pp. 1099–104. Epmc, doi:10.1073/pnas.1618364114.
Bracamonte-Baran W, Florentin J, Zhou Y, Jankowska-Gan E, Haynes WJ, Zhong W, Brennan TV, Dutta P, Claas FHJ, van Rood JJ, Burlingham WJ. Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance. Proceedings of the National Academy of Sciences of the United States of America. 2017 Jan;114(5):1099–1104.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

January 2017

Volume

114

Issue

5

Start / End Page

1099 / 1104

Related Subject Headings

  • T-Cell Antigen Receptor Specificity
  • Pregnancy
  • Models, Immunological
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Maternal-Fetal Exchange
  • Male
  • Isoantigens
  • Immune Tolerance