Resistance to cutaneous graft-vs.-host disease is not induced in T cell receptor delta gene-mutant mice.
The function of murine dendritic epidermal cells (dEC) remains largely speculative, probably because of the lack of a suitable in vivo model, although previous studies suggest that gamma/delta+ dEC may have originally evolved to serve as a self-protection mechanism(s). Our previous study demonstrated that the epidermis of mice that had spontaneously recovered from cutaneous graft-vs-host disease (GVHD) induced by local injection of CD4+ autoreactive T cells contained unexpectedly large numbers of dEC and became resistant to subsequent attempts to induce GVHD in a site-restricted manner, suggesting that the resistance is mediated by dEC. However, because alpha/beta+ dEC as well as gamma/delta+ dEC were greatly increased in number in the epidermis, it was unclear whether gamma/delta+ dEC are indeed responsible for this protection. The availability of this murine model and mice selectively lacking gamma/delta T cells as a result of disruption of the T cell receptor C delta gene segment allowed us to investigate the role of gamma/delta+ dEC. In the epidermis of gamma/delta T cell-deficient mice (delta-/-), a congenital lack of gamma/delta+ dEC was substituted for by alpha/beta+ dEC of either a CD4-8+ or a CD4-8- phenotype. After intradermal injection of the autoreactive T cells, delta-/- mice developed significantly enhanced delayed-type hypersensitivity responses and cutaneous GVHD, which persisted longer than in heterozygous littermate controls (delta+/-). Surprisingly, resistance to the cutaneous GVHD was not induced in the epidermis of delta-/- mice after spontaneous recovery from the GVHD, whereas the "susceptible" epidermis of delta-/+ mice contained large numbers of alpha/beta dEC comparable to those in "resistant" epidermis of delta+/- mice. Injection of day 16 fetal thymocytes from wild-type mice into delta-/- mice resulted in the appearance of donor-type gamma/delta+ dEC in the epidermis, and reconstitution with gamma/delta+ dEC restored the protective immune response of the epidermis against the GVHD to nearly normal levels. These results indicate that gamma/delta+ dEC are responsible for the site-restricted protection against cutaneous GVHD.
Shiohara
T
T
Department of Dermatology, Kyorin University School of Medicine, Tokyo, Japan.
Moriya
N
N
Hayakawa
J
J
Itohara
S
S
Ishikawa
H
H
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002999:Clone Cells; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology*; D006968:Hypersensitivity, Delayed; D007113:Immunity, Innate; D016219:Immunotherapy, Adoptive; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics*; D016038:Skin Transplantation / Q000276:immunology*
D016692:Receptors, Antigen, T-Cell, gamma-delta