Absence of innate MyD88 signaling promotes inducible allograft acceptance.
Prior experimental strategies to induce transplantation tolerance have focused largely on modifying adaptive immunity. However, less is known concerning the role of innate immune signaling in the induction of transplantation tolerance. Using a highly immunogenic murine skin transplant model that resists transplantation tolerance induction when innate immunity is preserved, we show that absence of MyD88, a key innate Toll like receptor signal adaptor, abrogates this resistance and facilitates inducible allograft acceptance. In our model, absence of MyD88 impairs inflammatory dendritic cell responses that reduce T cell activation. This effect increases T cell susceptibility to suppression mediated by CD4+ CD25+ regulatory T cells. Therefore, this study provides evidence that absence of MyD88 promotes inducible allograft acceptance and implies that inhibiting innate immunity may be a potential, clinically relevant strategy to facilitate transplantation tolerance.
Walker
Wendy E
WE
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Nasr
Isam W
IW
Camirand
Geoffrey
G
Tesar
Bethany M
BM
Booth
Carmen J
CJ
Goldstein
Daniel R
DR
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics*; D007113:Immunity, Innate; D008213:Lymphocyte Activation; D051379:Mice; D023421:Models, Animal; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency* / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014181:Transplantation Immunology / Q000276:immunology*; D014184:Transplantation, Homologous
C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88