Loss of T cell receptor-induced Bmi-1 in the KLRG1(+) senescent CD8(+) T lymphocyte.
Clones of CD8(+) T cells specific for viral antigens must avoid replicative senescence to maintain continuous production of new effector cells during chronic viral infections. In the present study, we have determined whether this capability may be related to Bmi-1, a transcriptional repressor that is required for the maintenance of hematopoietic stem cells and certain neural stem cells and that mediates its antisenescence function by inhibiting transcription of the Ink4a/Arf tumor suppressor locus. Ligation of the T cell receptor increased the levels of Bmi-1 mRNA and protein in primary CD8(+) T cells. The increased expression was reversible upon removal of antigen but could be maintained by using stimulation with the IL-2 receptor. Specific suppression of Bmi-1 by using a lentivirally encoded short hairpin RNA inhibited the proliferation of IL-2-stimulated CTLL-2 cytotoxic T cells and primary CD8(+) T cells. Ectopically expressed Bmi-1 enhanced the expansion of primary CD8(+) T cells stimulated by IL-2 and IL-7 in vitro and by homeostatic signals in vivo. Taken together, these findings indicate that Bmi-1 is required for CD8(+) T cell clonal expansion and is positively regulated by receptors that mediate this response. Therefore, the observation that the ability of the T cell receptor to induce Bmi-1 is maintained in the subset of replication-competent, antigen-experienced CD8(+) T cells that do not express the killer cell lectin-like receptor G1 (KLRG1) but is developmentally switched off in the senescent, KLRG1(+) subset suggests that Bmi-1 is a molecular determinant of the capacity of a CD8(+) T cell clone to persist during chronic viral infections.
Wellcome Trust Immunology Unit, Department of Medicine, University of Cambridge, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, United Kingdom.
Maike
M
Heffner
Douglas T
DT
Fearon
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D049109:Cell Proliferation; D016922:Cellular Senescence; D007156:Immunologic Memory; D037181:Lectins, C-Type; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000096:biosynthesis*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology*; D012097:Repressor Proteins / Q000096:biosynthesis*
C489421:Bmi1 protein, mouse; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1