title: Interleukin-2 reverses the defect in activation-induced apoptosis in T cells from autoimmune lpr mice.
abstract: Activated T cells from MRLlpr/lpr (lpr) mice have been shown to be resistant to TCR-induced apoptosis (activation-induced cell death) in vitro. We have found that this resistance is related to a defect in IL-2R alpha (CD25) expression and IL-2 signaling. Following primary activation, splenic T cells from 8-week old lpr mice failed to undergo apoptosis after the TCR was religated upon reculture with plate-bound anti-CD3 mAb. These cells had markedly reduced levels of IL-2 secretion and CD25 expression during primary activation in vitro; however, the cells still progressed through the cell cycle and were capable of cell division following TCR religation. Addition of exogenous IL-2 during the primary activation of 8-week-old lpr T cells overcame the defect in CD25 expression. Strikingly, these cells also became sensitive to apoptosis induction and died when the TCR was religated with anti-CD3 mAb. Viable cell recovery of both the lpr CD4+ and CD8+ subsets, as well as the CD4-CD8- subsets, was dramatically reduced under these conditions. Further investigation also revealed that the defect in activation-induced apoptosis in T cells from lpr mice was age-related. Activated T cells from young lpr mice (5 weeks old) underwent apoptosis in response to TCR ligation; these cells also expressed normal levels of CD25 following primary activation. However, as the mice aged from 5 to 8 weeks, susceptibility to TCR-mediated apoptosis in vitro was progressively lost together with the ability to express CD25. Our results suggest that before the onset of severe lymphoaccumulation, activated T cells from young lpr mice possess the capability to undergo TCR-induced apoptosis despite defective fas expression; IL-2 participates in sensitizing the cells to this death pathway. In older mice, this pathway breaks down and, together with the lack of fas-induced apoptosis, may account for the onset of severe lymphoaccumulation and autoimmunity.
authors.affiliation: Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Canada.
authors.forename: L G
authors.initials: LG
authors.lastname: Radvanyi
authors.forename: K
authors.initials: K
authors.lastname: Raju
authors.forename: D
authors.initials: D
authors.lastname: Spaner
authors.forename: G B
authors.initials: GB
authors.lastname: Mills
authors.forename: R G
authors.initials: RG
authors.lastname: Miller
mesh_terms: D000375:Aging / Q000276:immunology; D000818:Animals; D017209:Apoptosis; D015551:Autoimmunity / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D007376:Interleukin-2 / Q000276:immunology* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
chemical_list: D007376:Interleukin-2; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015375:Receptors, Interleukin-2