Stimulation of human EBV- and CMV-specific cytolytic effector function using allogeneic HLA molecules

• Published in: The Journal of immunology (1950) 2012-11, Vol.189 (10), p.4825-4831
• Main Authors: D'Orsogna, Lloyd J, van den Heuvel, Heleen, van der Meer-Prins, Ellen M W, Roelen, Dave L, Doxiadis, Ilias I N, Claas, Frans H J
• Format: Article
• Language: English
• Subjects: Cells, Cultured; Cytomegalovirus; Cytomegalovirus - immunology; Cytomegalovirus Infections - immunology; Epstein-Barr virus; Epstein-Barr Virus Infections - immunology; Female; Herpesvirus 4, Human - immunology; HLA-B Antigens - immunology; Humans; Immunologic Memory; Male; Peptides - immunology; T-Lymphocytes, Cytotoxic - immunology; Viral Proteins - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1201034

Viral infection is a major cause of morbidity and mortality, and there are few therapeutic options available to augment a virus-specific T cell response. Although allo-HLA cross-reactivity from virus-specific memory T cells is common, it is unclear whether priming with specific allogeneic cells could conversely elicit a viral peptide/self-HLA restricted cytotoxic T cell response in humans. First, we used the previously described allo-HLA-B*44:02 cross-reactivity of EBV peptide/HLA-B8 restricted T cells, to determine whether allogeneic HLA stimulation can elicit a cytolytic immune response against EBV. HLA-B8(+) HLA-B44(-) EBV-seropositive PBMCs were stimulated with either HLA-B*44:02(+) or HLA-B*44:03(+) mismatched irradiated PBMCs in a 7-10 d MLR. The allo-HLA stimulated responder cells were then evaluated for cytotoxicity using EBV peptide loaded autologous target cells and unloaded HLA-B8(+) EBV LCL target cells. PBMCs from EBV-seropositive donors gained EBV-specific cytolytic effector function following specific allo-HLA stimulation. Finally, we also elicited cytolytic CMV-specific responses using specific allogeneic cell stimulation, to confirm that this technique can be used to elicit viral peptide/self-HLA restricted responses even from nonpublic TCR responses. Allogeneic cell stimulation used as a cell therapy may be a potential tool to augment an antiviral T cell response in patients with EBV or CMV infection.