Regulation of T‐cell apoptosis: a mixed lymphocyte reaction model

Abstract

SUMMARYDespite the capacity for antigen-speci®c activation and rapid clonal expansion, homeostatic mechanisms ensure that the mature immune system contains a relatively stable number of T cells. In recent years, it has become apparent that this stability is a consequence of apoptotic death of most of the speci®c T cells generated during an immune response. Clearly this process must be tightly regulated in order to retain suf®cient T-cell progeny to mediate an effective response, whilst allowing the rapid deletion of these cells at the end of the response to prevent lymphadenopathy and cross-reactive autoimmunity. In this study, the factors that regulate the sensitivity of T cells to apoptosis were investigated in vitro after the induction of primary T-cell activation within a mixed lymphocyte reaction (MLR). It was found that activated T cells rapidly acquire the expression of both Fas and Fas ligand (FasL) on their surface and contain high levels of the precursor form of the pro-apoptotic enzyme, caspase 8 (FLICE). However, these T cells were resistant for up to 5 days to apoptosis following the stimulation of Fas; a maximal apoptotic response was observed after 7 days. This time point coincided with a marked reduction in expression of the FLICE inhibitory protein (FLIP) and maximal activity of caspase 8. At time points beyond day 7, the number of viable cells in the MLR decreased further despite a reduction in the expression of FasL. However, the expression of interleukin-2 (IL-2) at these late time points was low, resulting in a decrease in expression of the anti-apoptotic protein Bcl-2. This can produce apoptosis by allowing leakage of cytochrome-c from mitochondria resulting in direct activation of the caspase cascade. In this study, it is shown that T cells are resistant to apoptosis for the ®rst 5 days after activation as a consequence of insensitivity of the Fas pathway and the presence of intracellular Bcl-2. After between 5 and 7 days, the cells become sensitive to Fas-mediated apoptosis while retaining Bcl-2 expression. At later time points, Fas ligation is reduced but the cells respond to a decreased availability of IL-2 by reducing Bcl-2 expression; this encourages further apoptosis by allowing the direct activation of caspase enzymes.

CTLA-4 · FasL Induces Early Apoptosis of Activated T Cells by Interfering with Anti-Apoptotic Signals

“…Although activated T cells up-regulate Fas receptor (CD95) on their surfaces from the first day after activation, they become sensitive to proapoptotic triggering ligand (FasL) only at days 3-6 after stimulation (34 -36). The initial resistance to FasL-induced apoptosis is believed to be related to anti-apoptotic signals that emerge in the course of T cell stimulation (35,36). One critical anti-apoptotic protein appears to be the FLICE inhibitory protein, cFLIP (37,38,(41)(42)(43)(44).…”

Thymomegaly, Microsplenia, and Defective Homeostatic Proliferation of Peripheral Lymphocytes in p51-Ets1 Isoform-Specific Null Mice

“…In the thymus and peripheral lymphoid compartment, cellsurface receptor expression, cell division, and apoptosis exert strict controls on lymphocyte type and number. Lymphocyte homeostasis can control the balance between an insufficient number of cells to mount an immune response or the excessive proliferation and/or overstimulation of an immune response associated with pathological conditions, such as cancer and autoimmune disorders (16,42). Studies using antibodies to block CD44 function have demonstrated a role in lymphocyte activation, differentiation, homing/migration, and proliferation (15,21,31,44,47).…”

FLIP is expressed in mouse testis and protects germ cells from apoptosis

“…[22][23][24][25][26][27] Several studies show that it can prevent Fas-mediated apoptosis. In fact, while high c-FLIP levels reduce Fas-dependent arpoptosis in lymphocytes and melanoma, [28][29][30] c-FLIP downregulation makes lymphocytes more sensitive to Fas and affects self-tolerance. 31 Further, in dendritic cells, c-FLIP levels directly correlate with protection from Fas-mediated apoptosis.…”