Donor-derived cytomegalovirus-specific CD8+ T cells restricted to shared, donor-specific, or host-specific HLA after HLA mismatched hematopoietic stem cell transplantation

Kazuhiro Ikegame; Keiko Fukunaga; Yuko Osugi; Katsuji Kaida; Masahiro Teramoto; Takayuki Inoue; Masaya Okada; Kyoko Yoshihara; Hiroya Tamaki; Satoshi Yoshihara; Hiroshi Fujiwara

doi:10.1016/j.trim.2024.102099

Donor-derived cytomegalovirus-specific CD8⁺ T cells restricted to shared, donor-specific, or host-specific HLA after HLA mismatched hematopoietic stem cell transplantation

Transpl Immunol. 2024 Aug 5:87:102099. doi: 10.1016/j.trim.2024.102099. Online ahead of print.

Authors

Affiliations

¹ Department of Hematology, Hyogo Medical University, Hyogo, Japan; Hematopoietic Cell Transplantation Center, Aichi Medical University of School of Medicine, Aichi, Japan. Electronic address: kame@aichi-med-u.ac.jp.
² Department of Hematology, Hyogo Medical University, Hyogo, Japan; Department of Hematology, Nippon Medical school, Tokyo, Japan. Electronic address: Keiko-f@nms.ac.jp.
³ Department of Hematology, Hyogo Medical University, Hyogo, Japan. Electronic address: yu-oosugi@hyo-med.ac.jp.
⁴ Department of Hematology, Hyogo Medical University, Hyogo, Japan. Electronic address: kaidak@hyo-med.ac.jp.
⁵ Department of Hematology, Hyogo Medical University, Hyogo, Japan. Electronic address: ma-teramoto@hyo-med.ac.jp.
⁶ Department of Hematology, Hyogo Medical University, Hyogo, Japan. Electronic address: tinoue@hyo-med.ac.jp.
⁷ Department of Hematology, Hyogo Medical University, Hyogo, Japan; First Department of Internal Medicine, Kansai Medical University Medical Center, Osaka, Japan. Electronic address: masaya@hyo-med.ac.jp.
⁸ Department of Hematology, Hyogo Medical University, Hyogo, Japan. Electronic address: kyoko-y@hyo-med.ac.jp.
⁹ Department of Hematology, Hyogo Medical University, Hyogo, Japan. Electronic address: tamakhi@hyo-med.ac.jp.
¹⁰ Department of Hematology, Hyogo Medical University, Hyogo, Japan. Electronic address: yoshihar@hyo-med.ac.jp.
¹¹ Department of Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Mie, Japan. Electronic address: rieyunahiroshi@med.mie-u.ac.jp.

PMID: 39111366
DOI: 10.1016/j.trim.2024.102099

Abstract

Immune reconstitution after human leukocyte antigen (HLA)-mismatched (haploidentical) hematopoietic stem cell transplantation (haplo-HCT) can significantly influence long-term outcomes. The three possible HLA haplotypes after transplantation are: one carried by both the patient and the donor (shared HLA), one by donor only (donor-specific HLA), and one by patient only (host-specific HLA), and the donor T cells remain restricted to one of these three haplotypes. Understanding the presence of donor T cells restricted to each haplotype may provide more detailed insights into post-transplant immune response and potentially provide valuable information for the development of chimeric antigen receptor T cell or T cell receptor T cell constructs. In this study, patients or donors with HLA-A24 or HLA-A2 were tested with HLA-A*24:02- and A*02:01-restricted cytomegalovirus (CMV)-specific tetramers for detecting the respective HLA-restricted T cells. Sixty-four samples from 40 patients were assayed. More than half of the patients at day 90 and all patients by day 900 had shared HLA-restricted T cells. After day 90, half of the patients had donor-specific HLA-restricted T cells, but no host-specific HLA-restricted T cells were found. In the comparative analysis of the transplant types, shared HLA-restricted T cells were positive in all three categories: haplo-HCT (50%), 2-haplo-mis-HCT (75%), and spousal HCT (67%). Furthermore, donor-specific HLA-restricted T cells demonstrated positivity in haplo-HCT at 57% and in 2-haplo-mis-HCT at 60%, with a threshold of 0.01%. Donor-specific HLA-restricted T cells for spousal HCT were not examined due to the lack of an appropriate HLA combination for the tetramers. The presence of shared HLA-restricted T cells explains the host defense after HLA-haploidentical transplantation, while the presence of donor-specific HLA-restricted T cells may account for host defense against hematotropic viruses, such as CMV. However, this study failed to detect host-specific HLA-restricted T cells, leaving the host defense against epitheliotropic viruses unresolved, thus requiring further investigation.

Keywords: Donor-specific HLA; HLA mismatched transplantation; HLA restriction; Host-specific HLA; Shared HLA.