title: Dual receptor T cells mediate pathologic alloreactivity in patients with acute graft-versus-host disease.
abstract: Acute graft-versus-host disease (aGVHD) results from a robust response of donor T cells transferred during hematopoietic stem cell transplantation (HSCT) to allogeneic peptide-major histocompatibility complex antigens. Previous investigations have not identified T cell subsets that selectively mediate either protective immunity or pathogenic alloreactivity. We demonstrate that the small subset of peripheral T cells that naturally express two T cell receptors (TCRs) on the cell surface contributes disproportionately to aGVHD in patients after allogeneic HSCT. Dual TCR T cells from patients with aGVHD demonstrate an activated phenotype and produce pathogenic cytokines ex vivo. Dual receptor clones from a patient with symptomatic aGVHD responded specifically to mismatched recipient human leukocyte antigens (HLAs), demonstrating pathologic alloreactivity. Human dual TCR T cells are strongly activated and expanded by allogeneic stimulation in vitro, and disproportionately contribute to the repertoire of T cells recognizing both major (HLA) and minor histocompatibility antigens, providing a mechanism for their observed activity in vivo in patients with aGVHD. These results identify dual TCR T cells as a target for focused analysis of a T cell subset mediating GVHD and as a potential prognostic indicator.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA. pallen@wustl.edu
authors.forename: Gerald P
authors.initials: GP
authors.lastname: Morris
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Uy
authors.forename: David
authors.initials: D
authors.lastname: Donermeyer
authors.forename: John F
authors.initials: JF
authors.lastname: Dipersio
authors.forename: Paul M
authors.initials: PM
authors.lastname: Allen
mesh_terms: D000208:Acute Disease; D000911:Antibodies, Monoclonal / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology*; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D006680:HLA Antigens; D011948:Receptors, Antigen, T-Cell