Changes in sensitivity of peripheral lymphocytes of autoimmune gld mice to FasL-mediated apoptosis reveal a mechanism for the preferential deletion of CD4-CD8-B220+ T cells.
During thymic selection 'mis-selected' CD8(+) T cells exit to the periphery where they are deleted by a Fas/FasL-mediated mechanism, presumably as a result of activation by self-antigens. In the absence of functional FasL, as is the case in autoimmune gld mice, these 'mis-selected' T cells develop into unique Thy1(+)CD4(-)CD8(-) TCRalphabeta(+)B220(+) lymphocytes [abnormal double negative T (DN T) cells]. Using bioactive FasL-bearing vesicles [FasL vesicle preparation (FasL VP)], we were able to induce acute apoptosis in freshly isolated lymphocytes and to demonstrate that peripheral lymphocytes of gld mice become more sensitive to the FasL-mediated apoptosis as they age. Furthermore, flow cytometric analyses indicated that within this peripheral lymphocyte population, the abnormal DN T cells were preferentially eliminated. The exquisite sensitivity of these abnormal DN T cells is attributed to their increased membrane Fas expression with a concomitant reduction of cytosolic FLIP(L). Our data support the hypothesis that specific components of the Fas-mediated apoptotic pathway are modulated in favor of the elimination of auto-reactive T cells as well as those CD8(+) T cells that are 'mis-selected' in the thymus and escape to the periphery.
Xiao
Sheng
S
Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Zhang
Xingmin
X
Mann
Koren K
KK
Jodo
Satoshi
S
Li
Li
L
Jarjour
Wael N
WN
Marshak-Rothstein
Ann
A
Sherr
David H
DH
Ju
Shyr-Te
ST
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D058846:Antibodies, Monoclonal, Murine-Derived; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D001327:Autoimmune Diseases / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D017637:Clonal Deletion; D053222:Fas Ligand Protein; D015870:Gene Expression; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D017493:Leukocyte Common Antigens / Q000032:analysis; D008198:Lymph Nodes / Q000166:cytology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D008817:Mice, Mutant Strains; D011506:Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D013154:Spleen / Q000166:cytology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology; D051020:bcl-X Protein
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D051017:Apoptosis Regulatory Proteins; C494812:Bcl2l1 protein, mouse; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; C498892:Faim protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C411023:anti-Fas monoclonal antibody; D051020:bcl-X Protein; D017493:Leukocyte Common Antigens