Protection from autoimmune diabetes and T-cell lymphoproliferation induced by FasL mutation are differentially regulated and can be uncoupled pharmacologically.
Spontaneous mutation of Fas (lpr) or FasL (gld) completely protects nonobese diabetic mice from autoimmune diabetes but also causes massive double-negative T-cell lymphoproliferation. In this study, we used bone marrow chimeras and adoptive transfer analysis to investigate further the role of FasL in the pathogenesis of autoimmune diabetes and to determine whether gld-induced tolerance and double-negative T-cell lymphoproliferation can be uncoupled from each other. We show that FasL expressed on hematopoietic and nonhematopoietic compartments plays nonredundant roles in the pathogenesis of autoimmune diabetes. Mutation of FasL in either compartment interferes with the autoimmune process and prevents onset of diabetes, but FasL expressed in the hematopoietic compartment is the dominant regulator of T-cell homeostasis. Furthermore, pathogenesis of diabetes is dependent on normal FasL expression in both compartments, whereas only minimal FasL function is required to maintain T-cell homeostasis. Consequently, partial disruption of FasL protects from autoimmune diabetes without causing T-cell lymphoproliferation. This is demonstrated genetically in nonobese diabetic-gld/+ mice and pharmacologically by using FasL-neutralizing antibody. These results have important implications for understanding the role of the Fas pathway in pathogenesis of autoimmune diseases and for designing novel FasL-modulating therapies.
Mohamood
Abdiaziz S
AS
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Guler
Mehmet L
ML
Xiao
Zuoxiang
Z
Zheng
Dongfeng
D
Hess
Allan
A
Wang
Yi
Y
Yagita
Hideo
H
Schneck
Jonathan P
JP
Hamad
Abdel Rahim A
AR
D019264:Adoptive Transfer; D000818:Animals; D000974:Antibodies, Antinuclear / Q000032:analysis; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001854:Bone Marrow Cells; D002678:Chimera; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000517:prevention & control; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000517:prevention & control*; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D009154:Mutation; D013601:T-Lymphocytes / Q000502:physiology*
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D053222:Fas Ligand Protein