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

Maria V. Soares, Rita I. Azevedo, Inês A. Ferreira, Sara Bucar, Ana C. Ribeiro, Ana Vieira, Paulo N.G. Pereira, Ruy M. Ribeiro, Dario Ligeiro, Ana C. Alho, António S. Soares, Nádia Camacho, Carlos Martins, Fernanda Lourenço, Raul Moreno, Jerome Ritz, João F. Lacerda

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Abstract

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.

Original languageEnglish
Article number334
JournalFrontiers in Immunology
Volume10
Issue numberMAR
DOIs
Publication statusPublished - 2019

Fingerprint

T-Lymphocyte Subsets
T-Cell Antigen Receptor
Stem Cells
T-Lymphocytes
Transplants
Hematopoietic Stem Cell Transplantation
Unrelated Donors
Antilymphocyte Serum
Hematologic Neoplasms
Regulatory T-Lymphocytes
Homeostasis
Cell Proliferation
Apoptosis
Proteins

Keywords

  • Chronic graft vs. host disease
  • Hematopoietic stem cell transplantation
  • Immune reconstitution
  • Naive T cell
  • Stem cell memory
  • T lymphocyte

Cite this

Soares, Maria V. ; Azevedo, Rita I. ; Ferreira, Inês A. ; Bucar, Sara ; Ribeiro, Ana C. ; Vieira, Ana ; Pereira, Paulo N.G. ; Ribeiro, Ruy M. ; Ligeiro, Dario ; Alho, Ana C. ; Soares, António S. ; Camacho, Nádia ; Martins, Carlos ; Lourenço, Fernanda ; Moreno, Raul ; Ritz, Jerome ; Lacerda, João F. / 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. In: Frontiers in Immunology. 2019 ; Vol. 10, No. MAR.
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abstract = "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.",
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author = "Soares, {Maria V.} and Azevedo, {Rita I.} and Ferreira, {In{\^e}s A.} and Sara Bucar and Ribeiro, {Ana C.} and Ana Vieira and Pereira, {Paulo N.G.} and Ribeiro, {Ruy M.} and Dario Ligeiro and Alho, {Ana C.} and Soares, {Ant{\'o}nio S.} and N{\'a}dia Camacho and Carlos Martins and Fernanda Louren{\cc}o and Raul Moreno and Jerome Ritz and Lacerda, {Jo{\~a}o F.}",
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Soares, MV, Azevedo, RI, Ferreira, IA, Bucar, S, Ribeiro, AC, Vieira, A, Pereira, PNG, Ribeiro, RM, Ligeiro, D, Alho, AC, Soares, AS, Camacho, N, Martins, C, Lourenço, F, Moreno, R, Ritz, J & Lacerda, JF 2019, '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, vol. 10, no. MAR, 334. https://doi.org/10.3389/fimmu.2019.00334

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. / Soares, Maria V.; Azevedo, Rita I.; Ferreira, Inês A.; Bucar, Sara; Ribeiro, Ana C.; Vieira, Ana; Pereira, Paulo N.G.; Ribeiro, Ruy M.; Ligeiro, Dario; Alho, Ana C.; Soares, António S.; Camacho, Nádia; Martins, Carlos; Lourenço, Fernanda; Moreno, Raul; Ritz, Jerome; Lacerda, João F.

In: Frontiers in Immunology, Vol. 10, No. MAR, 334, 2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Soares, Maria V.

AU - Azevedo, Rita I.

AU - Ferreira, Inês A.

AU - Bucar, Sara

AU - Ribeiro, Ana C.

AU - Vieira, Ana

AU - Pereira, Paulo N.G.

AU - Ribeiro, Ruy M.

AU - Ligeiro, Dario

AU - Alho, Ana C.

AU - Soares, António S.

AU - Camacho, Nádia

AU - Martins, Carlos

AU - Lourenço, Fernanda

AU - Moreno, Raul

AU - Ritz, Jerome

AU - Lacerda, João F.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - Chronic graft vs. host disease

KW - Hematopoietic stem cell transplantation

KW - Immune reconstitution

KW - Naive T cell

KW - Stem cell memory

KW - T lymphocyte

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SN - 1664-3224

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