Regulation of apoptosis in mature alphabeta+CD4-CD8- antigen-specific suppressor T cell clones.
The regulation of apoptosis in mature CD4+ or CD8+ alphabeta+ T cells has been well studied. How the survival and death is regulated in peripheral CD4-CD8- (double negative, DN) alphabeta+ T cells remains unknown. Recent studies suggest that peripheral DN T cells may play an important role in the regulation of the immune responses mediated by CD4+ or CD8+ T cells. Here, we used immunosuppressive DN T cell clones to elucidate the mechanisms involved in the regulation of death and survival of alphabeta+ DN T cells. The DN T cell clones were generated from the spleen cells of 2C transgenic mice, which express the transgenic TCR specific for Ld and permanently accepted Ld+ skin allografts after pretransplant infusion of Ld+ lymphocytes. We report that 1) the mature DN T cells are highly resistant to TCR cross-linking-induced apoptosis in the presence of exogenous IL-4; 2) Fas/Fas-ligand and TNF-alpha/TNFR pathways do not play an apparent role in regulating apoptosis in DN T cells; 3) the DN T cells constitutively express a high level of Bcl-xL, but not Bcl-2; 4) both Bcl-xL and Bcl-2 are up-regulated following TCR-cross-linking; and 5) IL-4 stimulation significantly up-regulates Bcl-xL and c-Jun expression and leads to mitogen-activated protein kinase phosphorylation in DN T cells, which may contribute to the resistance to apoptosis in these T cells. Taken together, these results provide us with an insight into how mature DN T cells resist activation-induced apoptosis to provide a long-term suppressor function in vivo.
Khan
Q
Q
Department of Laboratory Medicine and Pathobiology, and Multi Organ Transplant Program, Toronto Hospital Research Institute, University of Toronto, Toronto, Ontario, Canada.
Penninger
J M
JM
Yang
L
L
Marra
L E
LE
Kozieradzki
I
I
Zhang
L
L
D000818:Animals; D017209:Apoptosis; D015704:CD4 Antigens / Q000302:isolation & purification*; D016827:CD8 Antigens / Q000302:isolation & purification*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002999:Clone Cells / Q000276:immunology; D053222:Fas Ligand Protein; D007152:Immunologic Capping; D015847:Interleukin-4 / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000302:isolation & purification; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000302:isolation & purification*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D051020:bcl-X Protein; D019014:fas Receptor / Q000378:metabolism
C494812:Bcl2l1 protein, mouse; D015704:CD4 Antigens; D016827:CD8 Antigens; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016755:Proto-Oncogene Proteins c-jun; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D019014:fas Receptor; D015847:Interleukin-4; D017871:Calcium-Calmodulin-Dependent Protein Kinases