Regulatory T cells inhibit CD8(+) T-cell tissue invasion in human skin graft-versus-host reactions.
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.


METHODS
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.


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.


CONCLUSIONS
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.
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. X.N.Wang@ncl.ac.uk
Emily
E
Mavin
Shaheda S
SS
Ahmed
Graeme
G
O'Boyle
Brie
B
Turner
Stephen
S
Douglass
Jean
J
Norden
Matthew
M
Collin
Simi
S
Ali
Anne
A
Dickinson
Xiao-Nong
XN
Wang
D000950:Antigens, Ly / Q000378:metabolism; D002448:Cell Adhesion; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000378:metabolism; D054371:Chemokine CXCL11 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D018920:Coculture Techniques; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006087:Graft vs Host Reaction / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D054367:Receptors, CXCR3 / Q000378:metabolism; D012867:Skin / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D046509:Tissue Culture Techniques
D000950:Antigens, Ly; C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D054367:Receptors, CXCR3; D007371:Interferon-gamma