Table 1.
T cell anergy versus T cell exhaustion.
Figure 1.
Mechanisms of T cell contraction after immune response resolution.
T cell contraction after resolution of an immune response is usually accomplished through a combination of mitochondria- and death receptor–dependent mechanisms. As a result of T cell expansion, survival factors as IL-2 become scarce, and signalling through survival pathways, like the phosphoinositide 3-kinase (PI3-K)/Akt pathway, ceases, allowing FoxO3-dependent Bim induction. Bim promotes mitochondrial outer membrane permeabilization (MOMP) by relieving the inhibitory effect that antiapoptotic Bcl-2 and Bcl-xL exert on proapoptotic Bax and Bak. MOMP results in cytochrome-c release from the mitochondria, enabling activation of a supramolecular complex, the apoptosome that activates caspase-3. By processing numerous cellular substrates, activated caspase-3 ensures completion of the execution phase of apoptosis. T cell activation also induces Fas ligand expression in T cells, which, by engaging the death receptor Fas, enables caspase-8 activation at the death-inducing signalling complex (DISC). Caspase-8 then activates caspase-3. If the levels of caspase-8–activated caspase-3 are not sufficient to undertake apoptotic cell death, a mitochondrial amplification loop may occur through caspase-8–mediated Bid cleavage. This generates tBid, a proapoptotic Bcl-2 family member that promotes MOMP by activating Bax and Bak.
Figure 2.
The uptake of apoptotic T lymphocytes by parasite-hosting phagocytes contributes to the remodelling of the parasite-hosting tissue as a bona fide protective niche.
Increased rates of T cell apoptosis occur during parasite infection, mediated either by death receptor– or mitochondria-dependent mechanisms. Upon clearance, these apoptotic cells induce an alternative state of activation in phagocytes associated with production of suppressive mediators as TGF-β and IL-10, as well as promoting parasite growth. Suppressive cytokines act on effector T cells and, together with antigen persistence and inhibitory T cell receptors, induce exhaustion of these cells. Additionally, inhibition of antigen presentation and costimulation, acting along with suppressive cytokines or enzymes (as IDO, which catabolizes tryptophan), may render naïve T cells anergic and unresponsive throughout infection. Eventually effector, anergic, or exhausted T cells undergo programmed cell death, fuelling the pool of apoptotic corpses and aiding perpetuation of the suppressive state.
Table 2.
Impact of targeted inhibition of suppressive or apoptotic T cell pathways in the outcome of parasitic infection.