Differential effects of peptide diversity and stromal cell type in positive and negative selection in the thymus.
Thymocyte positive selection results in maturation to the single-positive stage, while negative selection results in death by apoptosis. Although kinetic analyses indicate only 3-5% of CD4+ 8+ cells reach the single-positive stage, the balance of positive and negative selection and the nature and quantity of cells mediating maximal negative selection are uncertain. Here, using a system where the number and type of stromal cells and thymocytes can be controlled, we investigated the maturation of CD4+ 8+ thymocytes in the presence or absence of thymic epithelium and dendritic cells (DC) from wild-type (wt) and H-2M(-/-) mice expressing different peptide arrays. We find that titration of wt DC into reaggregates of wt epithelium has a dramatic effect on the number of CD4+ cells generated, with 1% DC causing a maximal 80% reduction. Moreover, while addition of 1% wt DC into cultures of H-2M(-/-) epithelium causes a 90% reduction in CD4+ cells, no effect was observed when similar numbers of wt thymic epithelium were added. Collectively, these data provide the first accurate indication of the quantity and quality of stromal cells required for maximal negative selection in the thymus, demonstrate the importance of peptide diversity in T cell selection, and highlight a large degree of overlap between positive and negative selection events.
Anderson
G
G
Department of Anatomy, Medical School, University of Birmingham, Edgbaston, United Kingdom.
Partington
K M
KM
Jenkinson
E J
EJ
D000818:Animals; D017951:Antigen Presentation; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D017637:Clonal Deletion / Q000502:physiology*; D003713:Dendritic Cells / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology; D006183:H-2 Antigens / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000276:immunology*; D017154:Stromal Cells / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology* / Q000196:embryology
D006183:H-2 Antigens; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments