Faculty Collaboration Database

Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance. Proc Natl Acad Sci U S A 2017 Jan 31;114(5):1099-1104

Date

01/18/2017

Pubmed ID

28096390

Pubmed Central ID

PMC5293109

DOI

10.1073/pnas.1618364114

Scopus ID

2-s2.0-85010932232 (requires institutional sign-in at Scopus site)   54 Citations

Abstract

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.

Author List

Bracamonte-Baran W, Florentin J, Zhou Y, Jankowska-Gan E, Haynes WJ, Zhong W, Brennan TV, Dutta P, Claas FH, van Rood JJ, Burlingham WJ

Author

Jonathan Florentin Research Scientist II in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adoptive Transfer
Animals
B7-2 Antigen
B7-H1 Antigen
CD4-Positive T-Lymphocytes
Chimerism
Dendritic Cells
Extracellular Vesicles
Female
Fetomaternal Transfusion
H-2 Antigens
Histocompatibility Antigen H-2D
Histocompatibility Antigens Class II
Immune Tolerance
Isoantigens
Male
Maternal-Fetal Exchange
Mice
Mice, Inbred C57BL
Mice, Transgenic
Models, Immunological
Pregnancy
T-Cell Antigen Receptor Specificity