Lung lymphocyte elimination by apoptosis in the murine response to intratracheal particulate antigen.
Pulmonary immune responses are suited to determine mechanisms of lymphocyte elimination, as lung inflammation must be regulated tightly to preserve gas exchange. The self-terminating response of primed C57BL/6 mice to intratracheal challenge with the T cell-dependent Ag sheep erythrocytes (SRBC) was used to test the importance of lung lymphocyte apoptosis in pulmonary immunoregulation. Apoptosis of alveolar and interstitial lymphocytes was demonstrated morphologically, by three independent methods to detect DNA fragmentation, and by surface expression of phosphatidylserine. Apoptotic lymphocytes were exclusively CD4-, CD8-, B220-, but many were CD3+ and Thy 1+. Inhibiting apoptosis by in vivo cyclosporine treatment prolonged lung lymphocyte accumulation following SRBC challenge. Experiments using mice homozygous for the lpr or gld mutations showed that pulmonary lymphocyte apoptosis depended on expression of Fas (CD95) and its ligand (Fas-L). Pulmonary inflammation increased on repeated intratracheal SRBC challenge of lpr/lpr mice, in contrast to the waning response in normal mice. These results confirm that in situ lymphocyte apoptosis contributes to termination of immune responses in nonlymphoid organs, probably because of activation-induced cell death, and may be important in inducing tolerance to repeated antigen exposure.
Milik
A M
AM
Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0760, USA.
Buechner-Maxwell
V A
VA
Sonstein
J
J
Kim
S
S
Seitzman
G D
GD
Beals
T F
TF
Curtis
J L
JL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000941:Antigens / Q000008:administration & dosage; D017209:Apoptosis / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D017252:CD3 Complex / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D016572:Cyclosporine / Q000494:pharmacology; D004247:DNA / Q000032:analysis; D053938:DNA Fragmentation; D004587:Electrophoresis, Agar Gel; D004912:Erythrocytes / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation; D017493:Leukocyte Common Antigens / Q000032:analysis; D008168:Lung / Q000276:immunology* / Q000648:ultrastructure; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008817:Mice, Mutant Strains; D010718:Phosphatidylserines / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D012756:Sheep; D013601:T-Lymphocytes / Q000276:immunology* / Q000648:ultrastructure; D018800:Thy-1 Antigens / Q000032:analysis; D019014:fas Receptor / Q000096:biosynthesis
D000911:Antibodies, Monoclonal; D000941:Antigens; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D007166:Immunosuppressive Agents; D010718:Phosphatidylserines; D011956:Receptors, Cell Surface; D018800:Thy-1 Antigens; D019014:fas Receptor; D016572:Cyclosporine; D004247:DNA; D017493:Leukocyte Common Antigens