Pro- and anti-apoptotic CD95 signaling in T cells

Abstract

The TNF receptor superfamily member CD95 (Fas, APO-1, TNFRSF6) is known as the prototypic death receptor in and outside the immune system. In fact, many mechanisms involved in apoptotic signaling cascades were solved by addressing consequences and pathways initiated by CD95 ligation in activated T cells or other "CD95-sensitive" cell populations. As an example, the binding of the inducible CD95 ligand (CD95L) to CD95 on activated T lymphocytes results in apoptotic cell death. This activation-induced cell death was implicated in the control of immune cell homeostasis and immune response termination. Over the past years, however, it became evident that CD95 acts as a dual function receptor that also exerts anti-apoptotic effects depending on the cellular context. Early observations of a potential non-apoptotic role of CD95 in the growth control of resting T cells were recently reconsidered and revealed quite unexpected findings regarding the costimulatory capacity of CD95 for primary T cell activation. It turned out that CD95 engagement modulates TCR/CD3-driven signal initiation in a dose-dependent manner. High doses of immobilized CD95 agonists or cellular CD95L almost completely silence T cells by blocking early TCR-induced signaling events. In contrast, under otherwise unchanged conditions, lower amounts of the same agonists dramatically augment TCR/CD3-driven activation and proliferation. In the present overview, we summarize these recent findings with a focus on the costimulatory capacity of CD95 in primary T cells and discuss potential implications for the T cell compartment and the interplay between T cells and CD95L-expressing cells including antigen-presenting cells.

Figure 1

CD95L-expressing APC down-modulate T cell responses. High density CD95L, as expressed on transfectants or certain activated APC or mimicked by high amounts of CD95 agonists in vitro, engages membrane CD95 and interferes with proximal TCR signaling by inhibiting the phosphorylation of ZAP-70, PLCγ and PKC, leading to inefficient nuclear translocation of transcription factors like NFAT, NF-κB and AP-1 (Jun/c-Fos). CD95 engagement under such conditions also prevents activation of caspases and MAPK as well as Ca²⁺-mobilization. Subsequently, TCR-induced cytokine production and upregulation of activation markers are impaired, resulting in a CD95L-mediated complete block of cell cycle progression in naïve T cells.

Figure 2

Dose-dependent effects of CD95 coligation on primary T cell activation. CD95 is capable of transducing non-apoptotic costimulatory signals in TCR/CD3-stimulated naïve T cells. Interestingly, the outcome of CD95 costimulation depends on the dose of agonist. Whereas high concentrations of CD95 agonists silence T cells, low doses augment TCR-induced activation and proliferation. Thus CD95 can act as a silencer or enhancer of primary T cell activation (see text for detail).

Figure 3

Costimulation with low doses of CD95 agonists increases primary T cell activation. CD95 coligation enhances MAPK and NF-κB activation in TCR-triggered cells and results in accelerated induction of activation markers, cell cycle regulatory proteins, cytokine secretion and cell cycle progression. The incomplete cleavage of caspase-3 into p20 fragments (possibly achieved by an interaction with XIAP) seems to be characteristic for non-apoptotic caspase activation and becomes more prominent upon CD95 costimulation. In line with the observed upregulation of anti-apoptotic proteins including cFLIP_R/S and Bcl-X_L in the presence of low dose CD95 agonists, CD95/TCR-stimulated cells display a partial apoptosis resistance.

Figure 4

Modulation of T cell responses through CD95 in naïve versus activated T cells. The activation state of a given T cell (population) defines the signal threshold for pro- or non- apoptotic CD95 signaling. At the next level, the signal strength passing through CD95 determines whether signal transduction results in cell death, survival, cell cycle arrest or enhanced proliferation. In naïve CD95-resistant T cells, CD95 acts as a potent costimulatory receptor that can transduce activatory or inhibitory signals depending on the dose of CD95 agonists to modulate TCR/CD3 signal induction. Activated T cells are CD95-sensitive and undergo apoptosis when exposed to high concentrations of CD95L. In contrast, a weak CD95 stimulus (again below a certain threshold level) might induce survival signaling in the absence of detectable cell death.