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Regulatory T cells inhibit CD8(+) T-cell tissue invasion in human skin graft-versus-host reactions.
- Source :
-
Transplantation [Transplantation] 2012 Sep 15; Vol. 94 (5), pp. 456-64. - Publication Year :
- 2012
-
Abstract
- Background: Regulatory T cells (Tregs) effectively ameliorate graft-versus-host disease (GVHD). The mechanisms underlying Treg therapeutic effect on GVHD are not fully elucidated. This study investigates whether Treg prevention of GVH tissue damage is associated with blocking CD8 effector T-cell tissue invasion, a question not yet addressed in humans.<br />Method: Tissue-infiltrating T cells and histopathology scores were detected using an in vitro human GVHD skin explant model, together with immunohistochemistry, cytometric bead array, functional adhesion and migration assays, flow cytometry, and quantitative real-time polymerase chain reaction.<br />Results: Treg intervention during priming significantly decreased effector T-cell infiltration into target tissue (P<0.01) resulting in a striking reduction in the histopathology score of tissue injury (P<0.0001). These results were coupled with reduced CXCR3 and cutaneous lymphocyte antigen expression by effector T cells, together with decreased CXCL10 and CXCL11 expression in target tissue. Treg intervention also impaired the functional interaction of CXCR3 and cutaneous lymphocyte antigen with their specific ligands (P<0.01) and suppressed the secretion of CXCL9, CXCL10, and interferon-γ (P<0.01, P<0.05, and P<0.001, respectively). Late addition of Tregs into the effector phase abolished their ability to suppress effector T-cell tissue invasion, resulting in a total loss of their ability to ameliorate GVH tissue damage.<br />Conclusion: Preventing effector T-cell tissue invasion is a critical mechanistic event leading to Treg attenuation of GVH tissue damage. This therapeutic effect is associated with a failure of CD8 T cells to increase tissue homing receptors after allo-stimulation, together with a breakdown of interferon-γ-induced chemoattractant expression in the target tissue.
- Subjects :
- Antigens, Ly metabolism
Cell Adhesion
Cells, Cultured
Chemokine CXCL10 metabolism
Chemokine CXCL11 metabolism
Chemokine CXCL9 metabolism
Coculture Techniques
Flow Cytometry
Graft vs Host Disease genetics
Graft vs Host Disease immunology
Graft vs Host Disease pathology
Humans
Immunohistochemistry
Interferon-gamma metabolism
Real-Time Polymerase Chain Reaction
Receptors, CXCR3 metabolism
Skin pathology
Tissue Culture Techniques
Chemotaxis, Leukocyte
Graft vs Host Disease prevention & control
Graft vs Host Reaction immunology
Skin immunology
T-Lymphocytes, Regulatory immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1534-6080
- Volume :
- 94
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Transplantation
- Publication Type :
- Academic Journal
- Accession number :
- 22890131
- Full Text :
- https://doi.org/10.1097/TP.0b013e31826205d6