Interleukin-2 Reverses the Defect in Activation-Induced Apoptosis in T Cells from AutoimmunelprMice

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-2Rα (CD25) expression and IL-2 signaling. Following primary activation, splenic T cells from 8-week-oldlprmice 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 activationin 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-oldlprT 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 thelprCD4+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 fromlprmice was age-related. Activated T cells from younglprmice (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 apoptosisin vitrowas progressively lost together with the ability to express CD25. Our results suggest that before the onset of severe lymphoaccumulation, activated T cells from younglprmice 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.