title: Direct and indirect antigen presentation lead to deletion of donor-specific T cells after in utero hematopoietic cell transplantation in mice.
abstract: In utero hematopoietic cell transplantation (IUHCTx) is a promising method to induce donor-specific tolerance but the mechanisms of antigen presentation that educate host T cells and the relative importance of deletion vs regulation in this setting are unknown. We studied the roles of direct and indirect antigen presentation (mediated by donor- and host-derived antigen-presenting cells [APCs], respectively) in a mouse model of IUHCTx. We found that IUHCTx leads to precocious maturation of neonatal host dendritic cells (DCs) and that there is early differentiation of donor-derived DCs, even after transplantation of a stem cell source without mature APCs. We next performed allogeneic IUHCTx into donor-specific T-cell receptor transgenic mice and confirmed that both direct and indirect antigen presentation lead to clonal deletion of effector T cells in chimeras. Deletion did not persist when chimerism was lost. Importantly, although the percentage of regulatory T cells (Tregs) after IUHCTx increased, there was no expansion in Treg numbers. In wild-type mice, there was a similar deletion of effector cells without expansion of donor-specific Tregs. Thus, tolerance induction after IUHCTx depends on both direct and indirect antigen presentation and is secondary to thymic deletion, without de novo Treg induction.
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine Department of Surgery, University of California-San Francisco, CA 94143, USA.
authors.forename: Amar
authors.initials: A
authors.lastname: Nijagal
authors.forename: Chris
authors.initials: C
authors.lastname: Derderian
authors.forename: Tom
authors.initials: T
authors.lastname: Le
authors.forename: Erin
authors.initials: E
authors.lastname: Jarvis
authors.forename: Linda
authors.initials: L
authors.lastname: Nguyen
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Tang
authors.forename: Tippi C
authors.initials: TC
authors.lastname: Mackenzie
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D005260:Female; D005313:Fetal Death / Q000276:immunology; D005315:Fetal Diseases / Q000276:immunology / Q000628:therapy; D005333:Fetus / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D007108:Immune Tolerance / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011247:Pregnancy; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000637:transplantation*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D018183:Transplantation Chimera / Q000276:immunology