Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD

The development and maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT) requires the balanced reconstitution of donor-derived CD4 regulatory T cells (CD4Tregs) as well as effector CD4 (conventional CD4 T cells [CD4Tcons]) and CD8 T cells. To characterize t...

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Bibliographic Details
Published in:Blood 2016-02, Vol.127 (5), p.646-657
Main Authors: Alho, Ana C., Kim, Haesook T., Chammas, Marie J., Reynolds, Carol G., Matos, Tiago R., Forcade, Edouard, Whangbo, Jennifer, Nikiforow, Sarah, Cutler, Corey S., Koreth, John, Ho, Vincent T., Armand, Philippe, Antin, Joseph H., Alyea, Edwin P., Lacerda, Joao F., Soiffer, Robert J., Ritz, Jerome
Format: Article
Language:English
Subjects:
Adult
Aged
CD4-Positive T-Lymphocytes - immunology
CD4-Positive T-Lymphocytes - pathology
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - pathology
Chronic Disease
Female
Graft vs Host Disease - etiology
Graft vs Host Disease - immunology
Graft vs Host Disease - pathology
Hematopoietic Stem Cell Transplantation - adverse effects
Humans
Male
Middle Aged
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - pathology
Transplantation
Transplantation, Homologous - adverse effects
Young Adult
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Summary:The development and maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT) requires the balanced reconstitution of donor-derived CD4 regulatory T cells (CD4Tregs) as well as effector CD4 (conventional CD4 T cells [CD4Tcons]) and CD8 T cells. To characterize the complex mechanisms that lead to unbalanced recovery of these distinct T-cell populations, we studied 107 adult patients who received T-replete stem cell grafts after reduced-intensity conditioning. Immune reconstitution of CD4Treg, CD4Tcon, and CD8 T cells was monitored for a 2-year period. CD3 T-cell counts gradually recovered to normal levels during this period but CD8 T cells recovered more rapidly than either CD4Tregs or CD4Tcons. Reconstituting CD4Tregs and CD4Tcons were predominantly central memory (CM) and effector memory (EM) cells and CD8 T cells were predominantly terminal EM cells. Thymic generation of naive CD4Tcon and CD8 T cells was maintained but thymic production of CD4Tregs was markedly decreased with little recovery during the 2-year study. T-cell proliferation was skewed in favor of CM and EM CD4Tcon and CD8 T cells, especially 6 to 12 months after HSCT. Intracellular expression of BCL2 was increased in CD4Tcon and CD8 T cells in the first 3 to 6 months after HSCT. Early recovery of naive and CM fractions within each T-cell population 3 months after transplant was also strongly correlated with the subsequent development of chronic graft-versus-host disease (GVHD). These dynamic imbalances favor the production, expansion, and persistence of effector T cells over CD4Tregs and were associated with the development of chronic GVHD. •Homeostatic recovery after allogeneic HSCT favors the production, expansion, and survival of effector T cells over CD4Tregs.•Unbalanced reconstitution of regulatory and effector T-cell subsets contributes to the development of chronic graft-versus-host disease.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2015-10-672345