Thymic and peripheral apoptosis of antigen-specific T cells might cooperate in establishing self tolerance.
Aside from CD4+CD8+ double-positive (DP) thymocytes, the subpopulations of T lineage cells affected by negative selection are unknown. To address whether this process occurs in more mature cell types, we have compared the responses of purified single-positive (SP) murine thymocytes and peripheral T cells to the superantigen staphylococcal enterotoxin B (SEB) utilizing as antigen-presenting cells (APC) a fibroblast cell line expressing transfected I-Ek class II molecules. Whereas approximately 70% of SEB-reactive SP thymocytes, either CD4+ or CD8+, undergo programmed cell death (apoptosis) and, therefore, negative selection, CD4+ and CD8+ antigen-specific peripheral T cells are predominantly activated and proliferate to APC+SEB. Thus, mature thymocytes and peripheral T cells, with identical patterns and levels of expression of CD4, CD8 and T cell receptor (TCR), are programmed to elicit different responses following TCR stimulation. Unexpectedly, however activation of peripheral T cells was preceded by deletion of a large fraction of V beta 8+ T lymphocytes (SEB specific). This surprising phenomenon was also observed in in vivo studies: in fact, administration of SEB to adult mice resulted in depletion of the majority of antigen-specific T cells from the peripheral lymphoid tissues analyzed (lymph nodes and spleen). This depletion is the consequence of deletion as indicated by program cell death of V beta 8+ T cells and is followed by proliferation of the remaining SEB-reactive T cells. Clonal elimination of peripheral T cells may represent a mechanism by which tolerance to self antigens never expressed in and/or exported to the thymus is achieved.
D'Adamio
L
L
Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston.
Awad
K M
KM
Reinherz
E L
EL
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D016827:CD8 Antigens / Q000032:analysis; D002454:Cell Differentiation; D002999:Clone Cells; D004768:Enterotoxins / Q000276:immunology; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology
D016827:CD8 Antigens; D004768:Enterotoxins; D009838:Oligodeoxyribonucleotides; D016693:Receptors, Antigen, T-Cell, alpha-beta; C031818:enterotoxin B, staphylococcal