title: Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance.
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.
authors.affiliation: Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792.
authors.forename: William
authors.initials: W
authors.lastname: Bracamonte-Baran
authors.affiliation: Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792.|Vascular Medicine Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Florentin
authors.affiliation: Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792.
authors.forename: Ewa
authors.initials: E
authors.lastname: Jankowska-Gan
authors.affiliation: Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792.
authors.forename: W John
authors.initials: WJ
authors.lastname: Haynes
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792.|Pathology and Laboratory Services, William S. Middleton Memorial Veterans Hospital, Madison, WI 53792.
authors.forename: Weixiong
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Division of Abdominal Transplantation, Department of Surgery, Duke University Medical Center, Durham, NC 27710.
authors.forename: Todd V
authors.initials: TV
authors.lastname: Brennan
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213.
authors.forename: Partha
authors.initials: P
authors.lastname: Dutta
authors.affiliation: Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
authors.forename: Frans H J
authors.initials: FH
authors.lastname: Claas
authors.affiliation: Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands Jon.vanRood@matchis.nl burlingham@surgery.wisc.edu.
authors.forename: Jon J
authors.initials: JJ
authors.lastname: van Rood
authors.affiliation: Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792; Jon.vanRood@matchis.nl burlingham@surgery.wisc.edu.
authors.forename: William J
authors.initials: WJ
authors.lastname: Burlingham
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000276:immunology; D060890:B7-H1 Antigen / Q000096:biosynthesis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D046528:Chimerism; D003713:Dendritic Cells / Q000276:immunology*; D000067128:Extracellular Vesicles / Q000276:immunology*; D005260:Female; D005331:Fetomaternal Transfusion / Q000276:immunology; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D064532:Histocompatibility Antigen H-2D / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance; D007519:Isoantigens / Q000276:immunology; D008297:Male; D008431:Maternal-Fetal Exchange / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018448:Models, Immunological; D011247:Pregnancy; D037182:T-Cell Antigen Receptor Specificity
chemical_list: D051940:B7-2 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C497965:Cd86 protein, mouse; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D064532:Histocompatibility Antigen H-2D; D000949:Histocompatibility Antigens Class II; C111389:I-Ad antigen; D007519:Isoantigens
keywords: T cells; dendritic cells; exosomes; microchimerism; split tolerance