title: Low-avidity CD8lo T cells induced by incomplete antigen stimulation in vivo regulate naive higher avidity CD8hi T cell responses to the same antigen.
abstract: We have previously reported that multiple injections of soluble MHC class I tetramers assembled with wild-type HY peptide induces unresponsiveness to male skin grafts in naive female C57BL/6 (B6) mice. Induction of unresponsiveness is dependent on a population of unresponsive allospecific CD8(lo )T cells. Reduced expression of CD8 acts to limit a T cell response to HY peptide by limiting the avidity window of effective signal transduction. We and others have demonstrated that CD8(lo) T cells are an alternative stable phenotype of CD8alphabeta(+) T cells in vitro and in vivo after antigen stimulation. We show here that CD8(lo) T cells can suppress naive CD8(+) T cell responses to HY antigen in vitro and male skin graft rejection in vivo after adoptive transfer into female recipients. These novel regulatory T cells express surface TGF-beta1 and secrete T cytotoxic 2 cytokines after antigen-specific stimulation. Anti-TGF-beta antibody and latency-associated peptide inhibit the suppressive effects in vitro. We also show that HY-specific memory CD8(+) T cells overcome regulation by CD8(lo) T cells. These data define a novel peripheral regulatory CD8(+ )T cell population that arises after repeated antigen encounter in vivo. These cells have implications in the maintenance of tolerance and memory.
authors.affiliation: Department of Surgery, University of North Carolina at Chapel Hill, 25799, USA. robmaile@bellsouth.net
authors.forename: Robert
authors.initials: R
authors.lastname: Maile
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Pop
authors.forename: Roland
authors.initials: R
authors.lastname: Tisch
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Collins
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Cairns
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Frelinger
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000008:administration & dosage* / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000008:administration & dosage* / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D016212:Transforming Growth Factor beta