Increased antigen presenting cell-mediated T cell activation in mice and patients without the autoimmune regulator.
Patients with autoimmune polyendocrine syndrome type I (APS I)suffer from endocrine and non-endocrine disorders due to mutations in the autoimmune regulator gene (AIRE). Mouse Aire is expressed both in thymic medullary epithelial cells and in peripheral antigen-presenting cells, suggesting a role in both central and peripheral tolerance. We here report that Aire(-/-) dendritic cells (DC) activate naive T cells more efficiently than do Aire(+/+) DC. Expression array analyses of Aire(-/-) DC revealed differential regulation of 68 transcripts, among which, the vascular cell adhesion molecule-1 (VCAM-1) transcript was up-regulated in Aire(-/-) DC. Concurrently, the expression of the VCAM-1 protein was up-regulated on both Aire(-/-) DC and monocytes from APS I patients. Blocking the interaction of VCAM-1 prevented enhanced Aire(-/-) DC stimulation of T cell hybridomas. We determined an increased number of DC in spleen and lymph nodes and of monocytes in the blood from Aire(-/-) mice, and an increased number of blood monocytes in APS I patients. Our findings imply a role for Aire in peripheral DC regulation of T cell activation, and suggest that Aire participates in peripheral tolerance.
Ramsey
Chris
C
Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA.
Hässler
Signe
S
Marits
Per
P
Kämpe
Olle
O
Surh
Charles D
CD
Peltonen
Leena
L
Winqvist
Ola
O
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D004700:Endocrine System Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency* / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology; D000096927:AIRE Protein
D014157:Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1; D000096927:AIRE Protein