Keratinocytes induce local tolerance to skin graft by activating interleukin-10-secreting T cells in the context of costimulation molecule B7-H1.
BACKGROUND
Intermingled skin grafting using autologous skin islets inlaid in allogeneic skin sheets was found to delay graft rejection, contributing to a significant reduction in mortality for patients with severe burns. In this study we examine the down-regulatory mechanisms underlying the effect of the autologous skin islets.


METHODS
Mixed culture of lymphocytes with epidermal cells of autologous and allogeneic origin were performed with a comparing of cell activity from cytokine-knockout mice. And the Th1/Th2-related cytokine profiles were examined.


RESULTS
Autologous keratinocytes act as potent inducers of suppression in the mixed culture by making a shift of the cytokine profile from Th1 to Th2. The observed suppression is predominantly mediated by interleukin (IL)-10, because the effect could be reversed by application of a neutralizing antibody to IL-10. The results of reconstitution experiments in BALB/c mice, with or without IL-10 gene-knockout, are consistent with this finding. These demonstrated that T cells were main effective components for the IL-10-related suppression. Furthermore, a newly identified member of the human B7 family (B7-H1) is found to play an important role in activating human IL-10-secreting lymphocytes. When transfected with the CD80 gene, autologous keratinocytes lost the ability to down-regulate the mixed cell culture, which effect could be reversed by introduction of the anti-CD80 antibody.


CONCLUSIONS
Our study provides new evidence that autologous keratinocytes present in intermingled skin grafts are inducers for local immune tolerance by expression of B1-H1 in their activation of the IL-10-secreting T cells.
Cao
Yingping
Y
Unit of Immunoregulation, Shanghai Institute of Immunology, Shanghai Second Medical University, Shanghai, China.
Zhou
Hong
H
Tao
Jian
J
Zheng
Zexian
Z
Li
Ningli
N
Shen
Baihua
B
Shih
Tsi-Siang
TS
Hong
Jian
J
Zhang
Jingwu
J
Chou
Kuang-Yen
KY
D000818:Animals; D015703:Antigens, CD; D018122:B7-1 Antigen / Q000494:pharmacology / Q000502:physiology*; D060890:B7-H1 Antigen; D001798:Blood Proteins; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000502:physiology; D006801:Humans; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015603:Keratinocytes / Q000502:physiology*; D008213:Lymphocyte Activation / Q000502:physiology*; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D010455:Peptides; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000502:physiology*; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D023001:Transplantation Tolerance
D015703:Antigens, CD; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; C423236:CD274 protein, human; C498919:Cd274 protein, mouse; D016207:Cytokines; D008562:Membrane Glycoproteins; D010455:Peptides; D016753:Interleukin-10