Theileria parva-transformed T cells show enhanced resistance to Fas/Fas ligand-induced apoptosis.
Lymphocyte homeostasis is regulated by mechanisms that control lymphocyte proliferation and apoptosis. Activation-induced cell death is mediated by the expression of death ligands and receptors, which, when triggered, activate an apoptotic cascade. Bovine T cells transformed by the intracellular parasite Theileria parva proliferate in an uncontrolled manner and undergo clonal expansion. They constitutively express the death receptor Fas and its ligand, FasL but do not undergo apoptosis. Upon elimination of the parasite from the host cell by treatment with a theilericidal drug, cells become increasingly sensitive to Fas/FasL-induced apoptosis. In normal T cells, the sensitivity to death receptor killing is regulated by specific inhibitor proteins. We found that anti-apoptotic proteins such as cellular (c)-FLIP, which functions as a catalytically inactive form of caspase-8, and X-chromosome-linked inhibitor of apoptosis protein (IAP) as well as c-IAP, which can block downstream executioner caspases, are constitutively expressed in T. parva-transformed T cells. Expression of these proteins is rapidly down-regulated upon parasite elimination. Antiapoptotic proteins of the Bcl-2 family such as Bcl-2 and Bcl-x(L) are also expressed but, in contrast to c-FLIP, c-IAP, and X-chromosome-linked IAP, do not appear to be tightly regulated by the presence of the parasite. Finally, we show that, in contrast to the situation in tumor cells, the phosphoinositide 3-kinase/Akt pathway is not essential for c-FLIP expression. Our findings indicate that by inducing the expression of antiapoptotic proteins, T. parva allows the host cell to escape destruction by homeostatic mechanisms that would normally be activated to limit the continuous expansion of a T cell population.
Küenzi
Peter
P
Division of Molecular Pathology, Institute of Animal Pathology, University of Bern, Bern, Switzerland.
Schneider
Pascal
P
Dobbelaere
Dirk A E
DA
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000096:biosynthesis; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D002461:Cell Line, Transformed; D004789:Enzyme Activation / Q000276:immunology; D053222:Fas Ligand Protein; D006706:Homeostasis / Q000276:immunology; D006790:Host-Parasite Interactions / Q000276:immunology; D007113:Immunity, Innate; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology*; D009285:Naphthoquinones / Q000494:pharmacology; D014176:Protein Biosynthesis; D011506:Proteins; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000469:parasitology*; D016797:Theileria parva / Q000187:drug effects / Q000254:growth & development / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology; D051636:X-Linked Inhibitor of Apoptosis Protein; D019014:fas Receptor / Q000096:biosynthesis / Q000502:physiology*
D000981:Antiprotozoal Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; D053222:Fas Ligand Protein; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D009285:Naphthoquinones; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D019014:fas Receptor; C046326:buparvaquone; D020169:Caspases