A role for accessibility to self-peptide-self-MHC complexes in intrathymic negative selection.
Whether intrathymic-positive and -negative selection of conventional alpha beta T cells occur in anatomically distinct sites is a matter of debate. By using a system composed of two distinct immune receptors, the Y-Ae mAb and the 1H3.1 (V alpha 1/V beta 6) TCR, both directed against the 52--68 fragment of the I-E alpha-chain (E alpha 52--68) bound to I-A(b), we examined the occurrence of negative selection imposed in vivo by a self-peptide-self-MHC class II complex with differential tissue expression. 1H3.1 TCR-transgenic (Tg) mice were bred to mice having an I-E alpha transgene with expression directed to all MHC class II-positive cells, restricted to thymic epithelial cells, or restricted to B cells, dendritic cells, and medullary thymic epithelial cells. All 1H3.1 TCR/I-E alpha double-Tg mice revealed a severely diminished thymic cellularity. Their lymph node cells were depleted of V beta 6(+)CD4(+) cells and were unresponsive to E alpha 52--68 in vitro. The absolute number of CD4(+)CD8(+) thymocytes was drastically reduced in all combinations, indicating that negative selection caused by an endogenously expressed self-determinant can effectively occur in the thymic cortex in vivo. Moreover, both cortical epithelial cells and, interestingly, the few cortical dendritic cells were able to support negative selection of CD4(+)CD8(+) thymocytes, albeit with a distinct efficiency. Collectively, these observations support a model where, in addition to the avidity of the thymocyte/stromal cell interaction, in vivo negative selection of autoreactive TCR-Tg T cells is determined by accessibility to self-peptide-self-MHC complexes regardless of the anatomical site.
Howard Hughes Medical Institute and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA.
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Viret
D B
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Sant'Angelo
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He
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Ramaswamy
C A
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Janeway
D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D017637:Clonal Deletion / Q000235:genetics; D003433:Crosses, Genetic; D018984:Epitopes, T-Lymphocyte / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010446:Peptide Fragments; D010455:Peptides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics; D017634:Self Tolerance / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D014998:Y Chromosome / Q000235:genetics / Q000276:immunology
D000954:Antigens, Surface; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D046911:Macromolecular Substances; D010446:Peptide Fragments; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; C117647:antigenic peptide Ealpha52-68