TNF-alpha impairs peripheral tolerance towards beta-cells, and local costimulation by B7.1 enhances the effector function of diabetogenic T cells.
Maintenance of peripheral tolerance and inactivation of autoreactive T cells is based on a delicate balance between pro-inflammatory and protective cytokines that is poorly understood. We have here addressed how the local expression of the inflammatory cytokine TNF-alpha can impair peripheral tolerance and lead to autoreactivity. After transplantation of pancreata that are immunogenic due to beta-cell expression of B7.1 and TNF-alpha, into thymectomized and euthymic syngeneic mice, we found that only euthymic mice rejected the grafts. This result suggests that under normal circumstances autoreactive T cells are functionally inactivated, and initiation of an autoreactive response requires de-novo generation of T cells. By contrast, thymectomized mice expressing TNF-alpha on the endogenous islets rejected the grafts, showing that expression of TNF-alpha prevents functional silencing of the autoreactive T cells. Thus, this study provides a mechanism by which TNF-alpha and possibly chronic inflammatory responses may promote autoimmune diseases. Furthermore, we have investigated whether B7.1 can enhance T cell responses of already activated T cells leading to islet rejection. By transplantation of wild-type and B7.1-expressing islets into overtly diabetic mice we found that only the wild-type islets could restore normoglycemia, suggesting that costimulation by B7.1 is required in the expansion or effector phase of the response.
Skak
Kresten
K
Department of Diabetes Autoimmunity, Hagedorn Research Institute, Gentofte, Denmark. skak@novonordisk.com
Guerder
Sylvie
S
Picarella
Dominic E
DE
Brenden
Nina
N
Flavell
Richard A
RA
Michelsen
Birgitte K
BK
D019264:Adoptive Transfer; D000818:Animals; D018122:B7-1 Antigen / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology*; D007108:Immune Tolerance; D007515:Islets of Langerhans / Q000473:pathology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013154:Spleen / Q000166:cytology; D013311:Streptozocin; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D018122:B7-1 Antigen; D014409:Tumor Necrosis Factor-alpha; D013311:Streptozocin