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.
Department of Diabetes Autoimmunity, Hagedorn Research Institute, Gentofte, Denmark. skak@novonordisk.com
Kresten
K
Skak
Sylvie
S
Guerder
Dominic E
DE
Picarella
Nina
N
Brenden
Richard A
RA
Flavell
Birgitte K
BK
Michelsen
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