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STEM CELL BIOLOGY

Frequent HLA-DR loss on hematopoietic stem progenitor cells in patients with cyclosporine-dependent aplastic anemia carrying HLA-DR15

Leukemia volume 36, pages 1666–1675 (2022)Cite this article

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A Correction to this article was published on 25 August 2023

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Abstract

To determine whether antigen presentation by HLA-DR on hematopoietic stem progenitor cells (HSPCs) is involved in the development of acquired aplastic anemia (AA), we studied the HLA-DR expression on CD45dimCD34+CD38+ cells in the peripheral blood of 61 AA patients including 23 patients possessing HLA-class I allele-lacking (HLA-class I[−]) leukocytes. HLA-DR-lacking (DR[−]) cells accounted for 13.0–57.1% of the total HSPCs in seven (11.5%) patients with HLA-DR15 who did not possess HLA-class I(–) leukocytes. The incubation of sorted DR(–) HSPCs in the presence of IFN-γ for 72 h resulted in the full restoration of the DR expression. A comparison of the transcriptome profile between DR(–) and DR(+) HSPCs revealed the lower expression of immune response-related genes including co-stimulatory molecules (e.g., CD48, CD74, and CD86) in DR(–) cells, which was not evident in HLA-class I(–) HSPCs. DR(–) cells were exclusively detected in GPI(+) HSPCs in four patients whose HSPCs could be analyzed separately for GPI(+) and GPI(–) HSPCs. These findings suggest that CD4+ T cells specific to antigens presented by HLA-DR15 on HSPCs may contribute to the development of AA as well as the immune escape of GPI(–) HSPCs in a distinct way from CD8+ T cells recognizing HLA-class I-restricted antigens.

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Fig. 1: The loss of the HLA-DR expression on hematopoietic stem progenitor cells (HSPCs) in the peripheral blood of acquired aplastic anemia (AA) patients carrying DR15.
Fig. 2: HLA-DR15 loss due to 6pLOH and its relationship with CsA dependency.
Fig. 3: Mechanisms underlying the HLA-DR loss on HSPCs and gene expression profiles unique to HLA-DR(-) HSPCs.
Fig. 4: The relationship between DR(-) HSPCs and GPI(-) HSPCs.

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Acknowledgements

This work was supported by MEXT KAKENHI (Grant-in-Aid for Scientific Research (B), Grant Number: 16H05335 and 19H03686) to SN, MEXT KAKENHI (Grant-in-Aid for Young Scientists (B), Grant Number: 19K17823) to KH, MEXT KAKENHI (Grant-in-Aid for Scientific Research (C), Grant Number: 21K08367) to KH. The authors thank the patients and donors and their physicians for contributing to this study and the Advanced Preventive Medical Sciences Research Center, Kanazawa University for the use of facilities. The authors thank Rie Ohmi (Kanazawa University) for her excellent technical assistance. We thank all patients and their physicians of participating institutions who contributed to this study. NT is a PhD candidate at Kanazawa University and this work is submitted in partial fulfillment of the requirements for the PhD.

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  1. These authors contributed equally: Noriaki Tsuji, Kohei Hosokawa.

Authors and Affiliations

  1. Department of Hematology, Faculty of Medicine, Institute of Medical Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan

    Noriaki Tsuji, Kohei Hosokawa, Ryota Urushihara, Mikoto Tanabe, Yoshitaka Zaimoku, Hiroyuki Takamatsu, Ken Ishiyama & Shinji Nakao

  2. Department of Clinical Laboratory Sciences, Kanazawa University Graduate School, Kanazawa, Japan

    Takamasa Katagiri

  3. Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan

    Tatsuhiko Ozawa & Hiroyuki Kishi

  4. Division of Transfusion Medicine, Kanazawa University Hospital, Kanazawa, Japan

    Hirohito Yamazaki

  5. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Seishi Ogawa

  6. Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden

    Seishi Ogawa

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  1. Noriaki Tsuji
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Contributions

NT, KH, and SN designed the research, analyzed the data, and wrote the manuscript. NT, KH, RU, MT, HT, KI, HY, and SN recruited patients and healthy volunteers to participate in the study. NT and KH performed flow cytometry. TK and SO performed SNP array analysis. TO, HK, RU, and HT generated anti-HLA-B61 monoclonal antibody. NT performed most of the in vitro experiments. NT and KH contributed equally to this work. All authors critically reviewed the manuscript and approved the submission of the final manuscript.

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Correspondence to Shinji Nakao.

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Tsuji, N., Hosokawa, K., Urushihara, R. et al. Frequent HLA-DR loss on hematopoietic stem progenitor cells in patients with cyclosporine-dependent aplastic anemia carrying HLA-DR15. Leukemia 36, 1666–1675 (2022). https://doi.org/10.1038/s41375-022-01549-6

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