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

Patrick J. Hanley, Jan J. Melenhorst, Sarah Nikiforow, Phillip Scheinberg, James W. Blaney, Gail Demmler-Harrison, C. Russell Cruz, Sharon Lam, Robert A. Krance, Kathryn S. Leung, Caridad A. Martinez, Hao Liu, Daniel C. Douek, Helen E. Heslop, Cliona M. Rooney, Elizabeth J. Shpall, A. John Barrett, Catherine M. Bollard

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number285ra63
JournalScience translational medicine
Volume7
Issue number285
DOIs
StatePublished - Apr 29 2015
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Hanley, P. J., Melenhorst, J. J., Nikiforow, S., Scheinberg, P., Blaney, J. W., Demmler-Harrison, G., Cruz, C. R., Lam, S., Krance, R. A., Leung, K. S., Martinez, C. A., Liu, H., Douek, D. C., Heslop, H. E., Rooney, C. M., Shpall, E. J., Barrett, A. J., & Bollard, C. M. (2015). CMV-specific T cells generated from naïve T cells recognize atypical epitopes and may be protective in vivo. Science translational medicine, 7(285), [285ra63]. https://doi.org/10.1126/scitranslmed.aaa2546