Naive and Stem Cell Memory T Cell Subset Recovery Reveals Opposing Reconstitution Patterns in CD4 and CD8 T Cells in Chronic Graft vs. Host Disease

Frontiers in Immunology

Jerome Ritz¹  Maria V. Soares²  Sara Bucar²  Ana C. Ribeiro²  Inês A. Ferreira²  Paulo N. G. Pereira²  Rita I. Azevedo²  António S. Soares²  Ruy M. Ribeiro³  Dario Ligeiro⁴  João F. Lacerda⁵  Ana C. Alho⁵  Nádia Camacho⁵  Carlos Martins⁵  Fernanda Lourenço⁵  Raul Moreno⁵  Ana Vieira⁶ 

[1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States;JLacerda Lab, Hematology and Transplantation Immunology, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal;Laboratório de Biomatemática, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal;Lisbon Centre for Blood and Transplantation, Instituto Português do Sangue e Transplantação, IP, Lisbon, Portugal;Serviço de Hematologia e Transplantação de Medula, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal;Unidade de Citometria de Fluxo, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal;

关键词: chronic graft vs. host disease;    hematopoietic stem cell transplantation;    T lymphocyte;    stem cell memory;    Naive T cell;    immune reconstitution;   

DOI  :  10.3389/fimmu.2019.00334

来源: DOAJ

【 摘 要 】

The success of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of hematological malignancies remains hampered by life-threatening chronic graft vs. host disease (cGVHD). Although multifactorial in nature, cGVHD has been associated with imbalances between effector and regulatory T cells (Treg). To further elucidate this issue, we performed a prospective analysis of patients undergoing unrelated donor allo-HSCT after a reduced intensity conditioning (RIC) regimen containing anti-thymocyte globulin (ATG) and the same GVHD prophylaxis, at a single institution. We studied T cell subset homeostasis over a 24-month follow-up after HSCT in a comparative analysis of patients with and without cGVHD. We also quantified naive and memory T cell subsets, proliferation and expression of the apoptosis-related proteins Bcl-2 and CD95. Finally, we assessed thymic function by T cell receptor excision circle (TREC) quantification and T cell receptor (TCR) diversity by TCRVβ spectratyping. While the total number of conventional CD4 (Tcon) and CD8 T cells was similar between patient groups, Treg were decreased in cGVHD patients. Interestingly, we also observed divergent patterns of Naive and Stem Cell Memory (SCM) subset recovery in Treg and Tcon compared to CD8. Patients with cGVHD showed impaired recovery of Naive and SCM Tcon and Treg, but significantly increased frequencies and absolute numbers of Naive and SCM were observed in the CD8 pool. Markedly increased EMRA CD8 T cells were also noted in cGVHD. Taken together, these results suggest that Naive, SCM and EMRA CD8 play a role in the emergence of cGHVD. Reduced Naive and recent thymic emigrant Tcon and Treg in cGVHD was likely due to impaired thymic output, as it was accompanied by decreased CD4 TREC and TCR diversity. On the other hand, CD8 TCR diversity was similar between patient groups. Furthermore, no correlation was observed between CD8 TREC content and Naive CD8 numbers, suggesting limited thymic production of Naive CD8 T cells in patients after transplant, especially in those developing cGVHD. The mechanisms behind the opposing patterns of CD4 and CD8 subset cell recovery in cGVHD remain elusive, but may be linked to thymic damage associated with the conditioning regimen and/or acute GVHD.

【 授权许可】

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