Impaired thymic negative selection causes autoimmune graft-versus-host disease.
Animal models with impaired thymic negative selection do not always cause autoimmune diseases despite the development of an autoreactive T-cell repertoire. We investigated the requirements for the development of systemic autoimmune disease by using bone marrow chimeras that lacked expression of major histocompatibility complex (MHC) class II on thymic antigen-presenting cells (APCs), leading to impaired negative selection. We found that impaired negative selection mediated by absence of MHC class II, but not MHC class I, permitted the development of systemic autoimmune disease that is indistinguishable from acute graft-versus-host disease (GVHD). Thymectomy prevented disease, confirming the causal association of the thymus with its development. Adoptive transfer of CD4+ T cells caused GVHD in secondary hosts only when they were irradiated, and cotransfer of peripheral CD4+ and CD8+ T cells from naive mice prevented the disease. These results demonstrate that impaired thymic negative selection can cause lethal autoimmune disease indistinguishable from acute GVHD in the context of a proinflammatory milieu when peripheral regulatory mechanisms are absent.
Teshima
Takanori
T
Department of Internal Medicine, University of Michigan Cancer Center, Ann Arbor, USA.
Reddy
Pavan
P
Liu
Chen
C
Williams
Debra
D
Cooke
Kenneth R
KR
Ferrara
James L M
JL
D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured / Q000276:immunology; D017637:Clonal Deletion; D003713:Dendritic Cells / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology / Q000528:radiation effects; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000502:physiology; D007375:Interleukin-1 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011828:Radiation Chimera; D011836:Radiation Tolerance; D017634:Self Tolerance / Q000276:immunology; D012867:Skin / Q000473:pathology; D013154:Spleen / Q000166:cytology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013934:Thymectomy; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014781:Viscera / Q000473:pathology
D018836:Inflammation Mediators; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha