A major role for host MHC class I antigen presentation for promoting islet allograft survival.
The purpose of this study was to determine the role for CD8 T cells versus generalized MHC class I-restricted antigen presentation in islet allograft rejection and tolerance. Diabetic C57BI/6 (B6, H-2(b)) controls, C57BI/6 CD8-deficient (CD8 KO), or MHC class I-deficient C57BI/6 (beta 2m KO) recipients were grafted with allogeneic BALB/c (H-2(d)) islets. Islet allografts were acutely rejected in untreated B6, CD8 KO, and in beta 2m KO mice, indicating that neither CD8 T cells nor host MHC class I is required for allograft rejection. We then determined the efficacy of costimulation blockade in these same strains. Costimulation blockade with anti-CD154 therapy facilitated long-term islet allograft survival in both B6 and in CD8 KO recipients. However, anti-CD154 treated beta 2m KO recipients were completely refractory to anti-CD154 therapy; all treated animals acutely rejected islet allografts with or without therapy. Also, anti-NK1.1 treatment of wild-type B6 mice abrogated graft prolongation following anti-CD154 therapy. Taken together, results show a dramatic distinction between two forms of MHC class I-restricted pathways in allograft prolongation. Although anti-CD154-induced allograft survival was CD8 T-cell independent, an intact host MHC class I-restricted (beta 2m-dependent) pathway is nevertheless necessary for allograft survival. This pathway required NK1.1+ cells, implicating NK and/or NKT cells in promoting allograft prolongation in vivo.
Beilke
J
J
The Barbara Davis Center for Childhood Diabetes/University of Colorado Health Sciences Center, Denver, 80262, USA.
Johnson
Z
Z
Kuhl
N
N
Gill
R G
RG
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000601:surgery*; D006085:Graft Survival; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014184:Transplantation, Homologous / Q000276:immunology*; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics / Q000276:immunology
D015395:Histocompatibility Antigens Class I; D001613:beta 2-Microglobulin