Induction and stability of the anergic phenotype in T cells

Abstract

One of the mechanisms that are in place to control the activation of mature T cells that bear self-reactive antigen receptors is anergy, a long-term state of hyporesponsiveness that is established in T cells in response to suboptimal stimulation. T cells receive signals that result not only from antigen recognition and costimulation but also from other sources, including cytokine receptors, inhibitory receptors or metabolic sensors. Integration of those signals will determine T cell fate. Under conditions that induce anergy, T cells activate a program of gene expression that leads to the production of proteins that block T cell receptor signaling and inhibit cytokine gene expression. In this review we will examine those signals that determine functional outcome following antigen encounter, review current knowledge of the factors that ensure signaling inhibition and epigenetic gene silencing in anergic cells and explore the mechanisms that lead to the reversal of anergy and the reacquisition of effector functions.

Keywords: Anergy induction; Anergy reversal; Epigenetics; NFAT.

Figure 1

Signal integration determines T cell fate. Activated T cells integrate signals triggered by recognition of MHC-antigen (Ag) complexes by the TCR, together with those induced by the engagement of CD28 by B7 ligands and by binding of IL-2 to the IL-2 receptor. Those signals translate into the activation of a series of signaling pathways, including increased calcium entry and activation of PKCθ, Ras/MAPKs, PI3K/AKT and mTOR, which allow the T cell to upregulate its metabolism and induce the transcription factors (e.g. NFAT, Fos/Jun or NFκB) required to maintain an activation-induced program of gene expression. When TCR engagement occurs in the absence of costimulation and/or the presence of inhibitory signals (e.g. effects of Tregs on DCs and effector T cells or engagement of coinhibitory receptors such as CTLA-4, PD-1 or A2aR) and unbalance activation of those signaling pathways leads to the induction of an alternative program of gene expression that will result in anergy.

Figure 2

NFAT proteins activate an anergy-inducing program of gene expression. In response to tolerizing stimuli, preferential activation of Ca²⁺-Calmodulin (Cm)-Calcineurin (Cn) signaling pathway leads to the expression of an NFAT-dependent program of gene expression. NFAT containing complexes, including NFAT1 homodimers, and other transcription factors, especially Egr proteins, will induce the expression of a series of proteins that will inhibit T cell activation at different levels. The ubiquitin ligases GRAIL, Itch and Cbl-b, caspase 3 and DGKα, will block TCR and CD28 signaling through targeted degradation or inactivation of multiple proteins that form part of the TCR signalosome. Sirt1 will directly deacetylate and inactivate Jun. Binding of transcriptional repressors, such as Ikaros (IK) or Tle4, to the Il2 and Ifng loci recruit chromatin remodeling proteins that together with DNA methyl transferases (DMT) will induce epigenetic modifications that will turn those genes into transcriptionally silenced loci.