Antigen-induced Pten gene deletion in T cells exacerbates neuropathology in experimental autoimmune encephalomyelitis.
The Pten tumor suppressor gene is critical for normal intrathymic development of T cells; however, its role in mature antigen-activated T cells is less well defined. A genetically crossed mouse line, Pten(fl/fl) GBC, in which Pten gene deletions could be primarily confined to antigen-activated CD8+ T cells, enabled us to evaluate the consequences of Pten loss on the course of experimental autoimmune encephalomyelitis. Compared with Pten(fl/fl) controls, myelin oligodendrocyte glycoprotein (MOG) peptide-immunized Pten(fl/fl) GBC mice developed more severe and protracted disease. This was accompanied by increased spinal cord white matter myelin basic protein depletion and axonal damage, as well as a striking persistence of macrophage and granzyme B-expressing cellular neuroinfiltrates in the chronic phase of the disease. This persistence may be explained by the observation that anti-CD3 activated Pten(fl/fl) GBC T cells were more resistant to proapoptotic stimuli. Consistent with the predicted consequences of Pten loss, purified CD8+ T cells from Pten(fl/fl) GBC mice displayed augmented proliferative responses to anti-T-cell receptor stimulation, and MOG-primed Pten(fl/fl) GBC T cells exhibited a reduced activation threshold to MOG peptide. Pten(fl/fl) GBC mice also developed atypical central nervous system disease, manifested by prominent cervical cord and forebrain involvement. Collectively, our findings indicate that the phosphatidylinositol 3-kinase signaling pathway is an essential regulator of CD8+ T-cell effector function in experimental autoimmune encephalomyelitis.
Johnson
Trina A
TA
Department of Biochemistry and Muscular Biology, McCaig Institute for Bone and Joint Health, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada.
Tsutsui
Shigeki
S
Jirik
Frank R
FR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001369:Axons / Q000187:drug effects / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology*; D017353:Gene Deletion; D017930:Genes, Reporter; D053804:Granzymes / Q000378:metabolism; D007114:Immunization; D007249:Inflammation; D019426:Integrases / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D063308:Myelin-Oligodendrocyte Glycoprotein; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology; D016548:Prosencephalon / Q000187:drug effects / Q000276:immunology; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology / Q000473:pathology
D017252:CD3 Complex; D016827:CD8 Antigens; D007376:Interleukin-2; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010455:Peptides; C045073:Cre recombinase; D019426:Integrases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D053804:Granzymes