T cell receptor (TCR)-induced death of immature CD4+CD8+ thymocytes by two distinct mechanisms differing in their requirement for CD28 costimulation: implications for negative selection in the thymus.
Negative selection is the process by which the developing lymphocyte receptor repertoire rids itself of autoreactive specificities. One mechanism of negative selection in developing T cells is the induction of apoptosis in immature CD4+CD8+ (DP) thymocytes, referred to as clonal deletion. Clonal deletion is necessarily T cell receptor (TCR) specific, but TCR signals alone are not lethal to purified DP thymocytes. Here, we identify two distinct mechanisms by which TCR-specific death of DP thymocytes can be induced. One mechanism requires simultaneous TCR and costimulatory signals initiated by CD28. The other mechanism is initiated by TCR signals in the absence of simultaneous costimulatory signals and is mediated by subsequent interaction with antigen-presenting cells. We propose that these mechanisms represent two distinct clonal deletion strategies that are differentially implemented during development depending on whether immature thymocytes encounter antigen in the thymic cortex or thymic medulla.
Punt
J A
JA
Experimental Immunology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
Havran
W
W
Abe
R
R
Sarin
A
A
Singer
A
A
D000818:Animals; D017951:Antigen Presentation; D015703:Antigens, CD / Q000235:genetics; D017209:Apoptosis / Q000502:physiology*; D015551:Autoimmunity / Q000502:physiology; D018122:B7-1 Antigen / Q000502:physiology; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D017637:Clonal Deletion / Q000502:physiology*; D053222:Fas Ligand Protein; D005260:Female; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D018448:Models, Immunological; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D015398:Signal Transduction / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000235:genetics / Q000502:physiology
D015703:Antigens, CD; D018122:B7-1 Antigen; D018106:CD28 Antigens; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor