title: Alloanergization of human T cells results in expansion of alloantigen-specific CD8(+) CD28(-) suppressor cells.
abstract: Allostimulation with concurrent costimulatory blockade induces alloantigen-specific hyporesponsiveness in responder T cells ("alloanergization"). Alloanergized responder cells also acquire alloantigen-specific suppressive activity, suggesting this strategy induces active immune tolerance. While this acquired suppressive activity is mediated primarily by CD4(+) FOXP3(+) cells, other cells, most notably CD8(+) suppressor cells, have also been shown to ameliorate human alloresponses. To determine whether alloanergization expands CD8(+) cells with allosuppressive phenotype and function, we used mixed lymphocyte cultures in which costimulatory blockade was provided by belatacept, an FDA-approved, second-generation CTLA-4-immunoglobulin fusion protein that blocks CD28-mediated costimulation, as an in vitro model of HLA-mismatched transplantation. This strategy resulted in an eightfold expansion of CD8(+) CD28(-) T cells which potently and specifically suppressed alloresponses of both CD4(+) and CD8(+) T cells without reducing the frequency of a range of functional pathogen-specific T cells. This CD8-mediated allosuppression primarily required cell-cell contact. In addition, we observed expansion of CD8(+) CD28(-) T cells in vivo in patients undergoing alloanergized HLA-mismatched bone marrow transplantation. Use of costimulatory blockade-mediated alloanergization to expand allospecific CD8(+) CD28(-) suppressor cells merits exploration as an approach to inducing or supporting immune tolerance to alloantigens after allogeneic transplantation.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: C M
authors.initials: CM
authors.lastname: Barbon
authors.forename: J K
authors.initials: JK
authors.lastname: Davies
authors.forename: A
authors.initials: A
authors.lastname: Voskertchian
authors.forename: R H
authors.initials: RH
authors.lastname: Kelner
authors.forename: L L
authors.initials: LL
authors.lastname: Brennan
authors.forename: L M
authors.initials: LM
authors.lastname: Nadler
authors.forename: E C
authors.initials: EC
authors.lastname: Guinan
mesh_terms: D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008213:Lymphocyte Activation; D014184:Transplantation, Homologous
chemical_list: D018106:CD28 Antigens; D007519:Isoantigens
keywords: Alloantigen-specific; CD8 suppresser cell; alloresponse; anergy; costimulatory molecule blockade; immune tolerance; regulatory T cell (Treg)