title: Promiscuity of the AlloHLA-A2 restricted T cell repertoire hampers the generation of minor Histocompatibility antigen-specific cytotoxic T cells across HLA barriers.
abstract: Hematopoietic system-specific miHAs are ideal targets for adoptive immunotherapy after allogeneic HLA (alloHLA)-matched SCT. Adoptive immunotherapy with cytotoxic T cells targeting hematopoietic system-specific miHAs restricted by alloHLA molecules is an attractive strategy to treat relapsed hematologic malignancies after HLA-mismatched SCT. As a proof of principle, we exploited 2 new strategies to generate alloHLA-A2-restricted miHA-specific T cells from HLA-A2(neg) donors using a HLA/miHA multimer-guided approach. In one strategy, autologous DCs coated with HLA-A2/miHA complexes were used for in vitro generation of miHA-specific T cells from HLA-A2(neg) male donors. In the other strategy, miHA-specific T cells were directly isolated from the peripheral blood of HLA-A2(neg) parous females with HLA-A2(pos) offspring. Both methods introduced recombinant HLA-A2/miHA complexes as the sole allogeneic target antigen. However, neither method yielded high avidity miHA-specific T cells or prevented the emergence of peptide-dependent promiscuous T cells. The latter T cells resembled miHA-specific T cells so closely with regard to tetramer binding and cytokine production that only extensive testing at a clonal level revealed their nonspecific nature. Therefore, promiscuity of the alloHLA-A2 T cell repertoire of HLA-A2(neg) individuals hampers in vitro generation of genuine miHA-specific T cells and limits its use for adoptive immunotherapy after HLA-A2 mismatched SCT.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands. l.e.m.oosten@lumc.nl
authors.forename: Liesbeth E M
authors.initials: LE
authors.lastname: Oosten
authors.forename: Els
authors.initials: E
authors.lastname: Blokland
authors.forename: Michel G D
authors.initials: MG
authors.lastname: Kester
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
authors.forename: Astrid G S
authors.initials: AG
authors.lastname: van Halteren
authors.forename: Els
authors.initials: E
authors.lastname: Goulmy
mesh_terms: D003713:Dendritic Cells / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods; D008297:Male; D009363:Neoplasm Proteins / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014184:Transplantation, Homologous / Q000009:adverse effects* / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; C080145:HA-2 antigen; D015789:HLA-A2 Antigen; D009363:Neoplasm Proteins