When an infection is effectively repelled by the adaptive immune system, two things occur. First, the actions of effector cells remove the pathogen and, with them, the antigens that originally stimulated their differentiation. Second, in the absence of antigen, most effector T cells undergo ‘death by neglect,’ removing themselves by apoptosis. The resulting ‘clonal contraction’ of effector T cells appears to be due both to the loss of pro-survival cytokines that are produced by antigenic stimulation, such as IL-2, and to the loss of expression of receptors for these cytokines. CD25, the IL-2 receptor component that mediates high-affinity binding, is transiently upregulated on antigen-activated T cells, but then declines, thus limiting IL-2 signaling in the absence of antigenic restimulation. Also, as is discussed in Section 11-21, most effector T cells lose expression of the specific component of the IL-7 receptor IL-7Rα (CD127) soon after activation. Like IL-2 signaling, IL-7 signaling activates STAT5, which promotes the expression of anti-apoptotic survival factors such as Bcl-2. Effector cells that lose responsiveness to IL-2 and IL-7 lose Bcl-2 and express Bim, which is a pro-apoptotic factor that acts via the intrinsic, or mitochondrial, pathway of apoptosis that leads to assembly of the apoptosome (see Sections 9-29 and 9-30).
While many effector T cells die from the loss of survival signals and the activation of the Bim-mediated intrinsic pathway of apoptosis, effector T-cell death can also occur via the extrinsic pathway of apoptosis that is activated by signaling via members of the TNF receptor superfamily, particularly Fas (CD95) (Fig. 11.22). Activation of the extrinsic pathway (or death receptor pathway) leads to the formation of the death-inducing signaling complex (DISC). The first step in Fas-mediated formation of the DISC is binding of the trimeric FasL, which results in the trimerization of Fas. This causes the death domains of Fas to bind to the death domain of FADD (Fas-associated via death domain), an adaptor protein introduced in Section 3-25. FADD contains a death domain and an additional domain called a death effector domain (DED) that can bind to DEDs present in other proteins. When FADD is recruited to Fas, the DED of FADD then recruits the initiator caspases pro-caspase 8 and pro-caspase 10 via interaction with a DED in the pro-caspases. The high local concentration of these caspases in association with activated receptors allows the caspases to cleave themselves, resulting in their activation. Once activated, caspases 8 and 10 are released from the receptor complex and can activate the downstream
Fig. 11.22 Binding of Fas ligand to Fas initiates the extrinsic panel). FADD also contains a domain called a death effector domain pathway of apoptosis. The cell-surface receptor Fas contains (DED) that allows it to recruit pro-caspase 8 or pro-caspase 10, (not a so-called death domain (DD) in its cytoplasmic tail. When Fas shown), which also contains a DED domain (right panel). Clustered ligand (FasL) binds Fas, this trimerizes the receptor (left panel). The pro-caspase 8 activates itself to release an active caspase into the adaptor protein FADD (also known as MORT-1) also contains a death cytoplasm (not shown). domain and can bind to the clustered death domains of Fas (center effector caspases that induce apoptosis. Loss-of-function mutations in Fas lead to the increased survival of lymphocytes and are one cause of the disease autoimmune lymphoproliferative syndrome (ALPS). This disease can also be due to mutations in FasL and in caspase 10.