Expression of tissue-specific autoantigens in the hematopoietic cells leads to activation-induced cell death of autoreactive T cells in the secondary lymphoid organs.
Many tissue-specific antigens are expressed in specialized cells called peripheral antigen-expressing cells (PAE) in the thymus and can induce central tolerance. While thymic medullary epithelial cells are the prototypic PAE that express peripheral antigens via an aire-dependent mechanism, some studies also describe bone marrow (BM)-derived dendritic cells (DC) and macrophages as PAE in both the thymus and secondary lymphoid organs. However, the role of these cells in development of tolerance to tissue-specific antigens has not been elucidated. Here we use BM radiation chimeric mice to study the existence of hematopoietic PAE and their contribution to tolerance to tissue-specific antigens. Our results reveal that BM-derived PAE exist in both central and secondary lymphoid organs and that the expression of peripheral antigens in the BM-derived cells does not correlate with aire expression. Using double-transgenic mice expressing TCR specific for a model antigen expressed under the control of a prostate-specific promoter, we show that expression of self antigen in PAE of non-hematopoietic origin is both necessary and sufficient to induce clonal deletion. Surprisingly, while BM-derived PAE fail to induce clonal deletion, they do cause the activation-induced cell death of autoreactive cells in the secondary lymphoid organs. Thus, BM-derived PAE have a distinct function in the maintenance of tolerance to tissue-specific antigens.
Zheng
Xincheng
X
Division of Cancer Immunology, Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
Yin
Lijie
L
Liu
Yang
Y
Zheng
Pan
P
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000276:immunology; D001324:Autoantigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D016923:Cell Death / Q000276:immunology; D006410:Hematopoiesis / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012313:RNA / Q000737:chemistry / Q000235:genetics; D011828:Radiation Chimera; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D014157:Transcription Factors / Q000276:immunology; D000096927:AIRE Protein
D000957:Antigens, Viral, Tumor; D001324:Autoantigens; D012313:RNA; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D000096927:AIRE Protein