title: Deletion of naïve T cells recognizing the minor histocompatibility antigen HY with toxin-coupled peptide-MHC class I tetramers inhibits cognate CTL responses and alters immunodominance.
abstract: Alloreactive T-cell responses directed against minor histocompatibility (H) antigens, which arise from diverse genetic disparities between donor and recipient outside the MHC, are an important cause of rejection of MHC-matched grafts. Because clinically significant responses appear to be directed at only a few antigens, the selective deletion of naïve T cells recognizing donor-specific, immunodominant minor H antigens in recipients before transplantation may be a useful tolerogenic strategy. We have previously demonstrated that peptide-MHC class I tetramers coupled to a toxin can efficiently eliminate specific TCR-transgenic T cells in vivo. Here, using the minor histocompatibility antigen HY as a model, we investigated whether toxic tetramers could inhibit the subsequent priming of the two H2-D(b)-restricted, immunodominant T-cell responses by deleting precursor CTL. Immunization of female mice with male bone marrow elicited robust CTL activity against the Uty and Smcy epitopes, with Uty constituting the major response. As hypothesized, toxic tetramer administration prior to immunization increased survival of cognate peptide-pulsed cells in an in vivo CTL assay, and reduced the frequency of corresponding T cells. However, tetramer-mediated decreases in either T-cell population magnified CTL responses against the non-targeted epitope, suggesting that D(b)-Uty(+) and D(b)-Smcy(+) T cells compete for a limited common resource during priming. Toxic tetramers conceivably could be used in combination to dissect manipulate CD8(+) T-cell immunodominance hierarchies, and to prevent the induction of donor-specific, minor H antigen CTL responses in allotransplantation.
authors.affiliation: Immunology Program, Department of Clinical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, NC 27607, USA.
authors.forename: Sabrina M
authors.initials: SM
authors.lastname: Hess
authors.forename: Ellen F
authors.initials: EF
authors.lastname: Young
authors.forename: Keith R
authors.initials: KR
authors.lastname: Miller
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Vincent
authors.forename: Adam S
authors.initials: AS
authors.lastname: Buntzman
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Collins
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Frelinger
authors.forename: Paul R
authors.initials: PR
authors.lastname: Hess
mesh_terms: D064591:Allografts; D000818:Animals; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D006182:H-Y Antigen / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D000922:Immunotoxins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D008212:Lymphocyte Depletion / Q000379:methods*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology
chemical_list: D018984:Epitopes, T-Lymphocyte; D006182:H-Y Antigen; D015395:Histocompatibility Antigens Class I; D000922:Immunotoxins; D010455:Peptides
keywords: APC; Alloreactivity; CFSE; Cytotoxic T lymphocytes; H; IP; IV; Immunodominance; LCMV; MFI; MHC; Minor histocompatibility antigens; PBL; PBSE; PE; Pacific Blue succinimidyl ester; SAP; Tetramers; YFP; YFP-enhanced transcript for IFN-γ; Yeti; allophycocyanin; carboxyfluorescein diacetate succinimidyl ester; histocompatibility; intraperitoneally; intravenously; lymphocytic choriomeningitis virus; mean fluorescence intensity; peripheral blood lymphocyte; phycoerythrin; saporin; yellow fluorescent protein