Anergy is T-cell unresponsiveness resulting from antigen recognition without costimulation. Tregs may induce anergy by reducing costimulation, but the same type of unresponsiveness may be seen in other situations that are not dependent on Tregs (Fig. 1).
Fig1. Mechanisms of T-cell anergy. (A) T-cell responses are induced when the cells recognize an antigen presented by an antigen-presenting cell (APC) and activating receptors on the T cells (such as CD28) recognize costimulators on the APCs (such as B7). (B) If the T cell recognizes a self antigen without costimulation, the T cell becomes unresponsive to the antigen because of a block in signaling from the T-cell receptor (TCR) complex or engagement of inhibitory receptors (such as CTLA-4 [cytotoxic T-lymphocyte antigen 4] and PD-1 [programmed cell death protein–1]). The signaling block may be the result of recruitment of phosphatases to the TCR complex or the activation of ubiquitin ligases that degrade signaling proteins. The T cell remains viable but is unable to respond to the self antigen. DC, Dendritic cell.
• Dendritic cells and other APCs in normal uninfected tissues and secondary lymphoid organs are normally in a resting (or immature) state, in which they express little or no costimulators. The low level of B7 expression is likely an intrinsic property of resting DCs and is reinforced by the ability of Tregs to block and remove B7 from the surface of APCs. These dendritic cells constantly process and display the self antigens that are present in these tissues. T lymphocytes with receptors for these self antigens are able to recognize the antigens and thus receive signals from their antigen receptors (signal 1), but the T cells do not receive strong costimulation (signal 2) and do not respond. In infections and following vaccination with adjuvants, APCs are activated by innate immune signaling and they increase the expression of costimulators, leading to effective immune responses.
Thus, the presence or absence of costimulation is a major fac tor determining whether T cells are activated or tolerized.
• Several cell-intrinsic signals promote T-cell unresponsiveness. The inhibitory receptor PD-1 is expressed on T cells in response to antigen recognition. When PD-1 engages its ligands, which are expressed on APCs and other cell types, it binds to and activates a tyrosine phosphatase that inhibits tyrosine kinase dependent signals from the TCR complex and CD28 (see Chapter 9). Thus, PD-1 limits activation by persistent stimuli, such as some microbes, tumors, and self antigens. This phe nomenon has been called exhaustion because the T cells initially make an effective response but the response is short-lived. The blockade of PD-1 for cancer immunotherapy induces autoimmune reactions that may be severe.
• The activation of ubiquitin ligases such as CBL-b in T cells responding to antigens also limits and terminates activation. CBL-b targets TCR- and CD28-associated signaling molecules for degradation, and thus inhibits T-cell activation. Genome-wide association studies have revealed variants of CBL-b in patients with multiple sclerosis and type I diabetes.
Deletion of T Cells by Apoptotic Cell Death
T lymphocytes that recognize self antigens with high affinity or are repeatedly stimulated by antigens may die by apoptosis. There are two major pathways of apoptosis: the mitochondrial (intrinsic) and death receptor (extrinsic) pathways, both of which have been implicated in peripheral deletion of mature T cells. The best evidence for the involvement of the two apoptotic pathways in the elimination of mature self-reactive lymphocytes is that genetic ablation of either in mice results in systemic auto immunity, and the disease is more severe if both pathways are disabled. Mutations of FAS, FAS-L, or caspases activated by FAS signaling cause a human autoimmune disease called autoimmune lymphoproliferative syndrome (ALPS). These two death path ways may function in different ways to maintain self-tolerance.
• T cells that recognize self antigens in the absence of costimu lation may undergo apoptosis by the mitochondrial pathway. In normal immune responses, the responding lymphocytes receive signals from the TCR, costimulators, and growth factors. These signals stimulate the expression of antiapoptotic proteins of the BCL-2 family (BCL-2, BCL-XL ) and thus prevent apoptosis and promote cell survival, the necessary prelude to proliferation. When T cells avidly recognize self antigens, they may activate BIM, which triggers death by the mitochondrial pathway. At the same time, because of the relative lack of costimulation and growth factors, the anti apoptotic members of the BCL-2 family remain at low levels, and the actions of the effectors BAX and BAK are thus not counteracted. The BIM-dependent mitochondrial pathway of apoptosis is also involved in negative selection of self-reactive T cells in the thymus (described earlier) and in the contraction phase (decline) of immune responses after the initiating antigen has been eliminated.
• Repeated stimulation of T cells results in coexpression of the death receptor FAS and its ligand FAS-L, and engagement of FAS triggers apoptosis.
