CMV-specific T cells generated from naïve T cells recognize atypical epitopes and may be protective in vivo

• Published in: Science translational medicine Vol. 7; no. 285; p. 285ra63
• Main Authors: Hanley, Patrick J, Melenhorst, Jan J, Nikiforow, Sarah, Scheinberg, Phillip, Blaney, James W, Demmler-Harrison, Gail, Cruz, C Russell, Lam, Sharon, Krance, Robert A, Leung, Kathryn S, Martinez, Caridad A, Liu, Hao, Douek, Daniel C, Heslop, Helen E, Rooney, Cliona M, Shpall, Elizabeth J, Barrett, A John, Rodgers, John R, Bollard, Catherine M
• Format: Journal Article
• Language: English
• Published: United States 29.04.2015
• Subjects: Cytomegalovirus - immunology; Cytomegalovirus - physiology; Epitopes - immunology; Humans; Receptors, Antigen, T-Cell - immunology; T-Lymphocytes - virology
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.aaa2546

Adoptive transfer of cytomegalovirus (CMV)-specific T cells derived from adult seropositive donors can effectively restore antiviral immunity after transplantation. However, CMV-seronegative donors lack CMV-specific memory T cells, which restricts the availability of virus-specific T cells for immunoprophylaxis. We demonstrate the feasibility of deriving CMV-specific T cells from naïve cells for T cell therapy. Naïve T cells primed to recognize CMV were restricted to different, atypical epitopes than T cells derived from CMV-seropositive individuals; however, these two cell populations had similar avidities. CMV-seropositive individuals also had T cells recognizing these atypical epitopes, but these cells had a lower avidity than those derived from the seronegative subjects, which suggests that high-avidity T cells to these epitopes may be lost over time. Indeed, recipients of cord blood (CB) grafts who did not develop CMV were found by clonotypic analysis to have T cells recognizing atypical CMVpp65 epitopes. Therefore, we examined unmanipulated CB units and found that T cells with T cell receptors restricted by atypical epitopes were the most common, which may explain why these T cells expanded. When infused to recipients, naïve donor-derived virus-specific T cells that recognized atypical epitopes were associated with prolonged periods of CMV-free survival and complete remission. These data suggest that naïve-derived T cells from seronegative patients may be an additional source of cells for CMV immunoprophylaxis.