Cross-recognition of HLA DR4 alloantigen by virus-specific CD8+ T cells: a new paradigm for self-/nonself-recognition

• Published in: Blood Vol. 114; no. 11; pp. 2244 - 2253
• Main Authors: Rist, Michael, Smith, Corey, Bell, Melissa J., Burrows, Scott R., Khanna, Rajiv
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 10.09.2009; Americain Society of Hematology
• Subjects: Autoimmunity - immunology; Biological and medical sciences; CD8-Positive T-Lymphocytes - immunology; Cell Line, Transformed; Cytomegalovirus - immunology; Epitopes, T-Lymphocyte - immunology; Graft Rejection - immunology; Hematologic and hematopoietic diseases; HLA-C Antigens - immunology; HLA-DR4 Antigen - immunology; Humans; Medical sciences; Peptides - immunology; Phosphoproteins - immunology; Receptors, Antigen, T-Cell, alpha-beta - immunology; Transplantation, Homologous; Viral Matrix Proteins - immunology; Virus; HLA-System; Death receptor 4; Alloantigen; Hematology; Major histocompatibility system; CD8 T lymphocyte
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-05-222596

The ability of CD8+ T cells to engage a diverse range of peptide–major histocompatibility complex (MHC) complexes can also lead to cross-recognition of self and nonself peptide-MHC complexes and thus directly contribute toward allograft rejection or autoimmunity. Here we present a novel form of cross-recognition by herpes virus–specific CD8+ cytotoxic T cells that challenges the current paradigm of self/non-self recognition. Functional characterization of a human leukocyte antigen (HLA) Cw*0602-restricted cytomegalovirus-specific CD8+ T-cell response revealed an unusual dual specificity toward a pp65 epitope and the alloantigen HLA DR4. This cross-recognition of HLA DR4 alloantigen was critically dependent on the coexpression of HLA DM and was preferentially directed toward the B-cell lineage. Furthermore, allostimulation of peripheral blood lymphocytes with HLA DRB*0401-expressing cells rapidly expanded CD8+ T cells, which recognized the pp65 epitope in the context of HLA Cw*0602. T-cell repertoire analysis revealed 2 dominant populations expressing T-cell receptor beta variable (TRBV)4-3 or TRBV13, with cross-reactivity exclusively mediated by the TRBV13+ clonotypes. More importantly, cross-reactive TRBV13+ clonotypes displayed markedly lower T-cell receptor binding affinity and a distinct pattern of peptide recognition, presumably mimicking a structure presented on the HLA DR4 allotype. These results illustrate a novel mechanism whereby virus-specific CD8+ T cells can cross-recognize HLA class II molecules and may contribute toward allograft rejection and/or autoimmunity.