CMV-specific T cells generated from naïve T cells recognize atypical epitopes and may be protective in vivo.
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.
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Program for Cell Enhancement and Technologies for Immunotherapy, The Sheikh Zayed Institute for Pediatric Surgical Innovation, the Center for Cancer and Immunology Research, and the Division of Blood and Marrow Transplantation, Children's National Health System and The George Washington University, Washington, DC 20052, USA.
Patrick J
PJ
Hanley
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Jan J
JJ
Melenhorst
Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St., Boston, MA 02115, USA.
Sarah
S
Nikiforow
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Phillip
P
Scheinberg
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA.
James W
JW
Blaney
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Gail
G
Demmler-Harrison
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Program for Cell Enhancement and Technologies for Immunotherapy, The Sheikh Zayed Institute for Pediatric Surgical Innovation, the Center for Cancer and Immunology Research, and the Division of Blood and Marrow Transplantation, Children's National Health System and The George Washington University, Washington, DC 20052, USA.
C Russell
CR
Cruz
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Program for Cell Enhancement and Technologies for Immunotherapy, The Sheikh Zayed Institute for Pediatric Surgical Innovation, the Center for Cancer and Immunology Research, and the Division of Blood and Marrow Transplantation, Children's National Health System and The George Washington University, Washington, DC 20052, USA.
Sharon
S
Lam
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Robert A
RA
Krance
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Kathryn S
KS
Leung
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Caridad A
CA
Martinez
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA.
Hao
H
Liu
Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Daniel C
DC
Douek
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Helen E
HE
Heslop
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
Cliona M
CM
Rooney
Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX 77030, USA.
Elizabeth J
EJ
Shpall
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
A John
AJ
Barrett
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
John R
JR
Rodgers
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030, USA. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Program for Cell Enhancement and Technologies for Immunotherapy, The Sheikh Zayed Institute for Pediatric Surgical Innovation, the Center for Cancer and Immunology Research, and the Division of Blood and Marrow Transplantation, Children's National Health System and The George Washington University, Washington, DC 20052, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. cbollard@cnmc.org.
Catherine M
CM
Bollard
D003587:Cytomegalovirus / Q000276:immunology / Q000502:physiology*; D000939:Epitopes / Q000276:immunology*; D006801:Humans; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000821:virology*
D000939:Epitopes; D011948:Receptors, Antigen, T-Cell