Molecular mechanisms of CD4+ T-cell anergy

In vitro clonal T-cell anergy is induced in previously activated T cells or T-cell clones by restimulation through the T-cell receptor (TCR) in the absence of co-stimulatory signals. This suboptimal signalling produces long-lived effects, such as reduced proliferation and cytokine production.Early molecular studies of anergic T cells found reduced amounts of the activator protein 1 (AP1) heterodimer in the nucleus coupled with normal translocation to the nucleus of nuclear factor of activated T cells (NFAT). Subsequent evidence suggested the requirement for calcium flux and the potential for expression of proteins enriched specifically by the anergic programme to induce T-cell anergy.Recent work identified important roles for linker for activation of T cells (LAT) palmitoylation, diacylglycerol (DAG) signalling, and transcription factors for the induction of both in vitro and in vivo T-cell anergy.Using the calcium ionophore ionomycin to simulate calcium flux and promote NFAT nuclear translocation without co-stimulation events, a group of E3 ubiquitin ligases — Casitas B-lineage lymphoma B (CBL-B), gene related to anergy in lymphocytes (GRAIL) and ITCH (itchy homologue E3 ubiquitin protein ligase) — were found to be enriched in anergic T cells. These members of the ubiquitin–proteasome pathway were also identified in other model systems of in vitro and in vivo T-cell anergy, and their ability to induce T-cell anergy depends on their E3 ubiquitin ligase activity.CBL-B ubiquitylation affects various signalling pathways including the phosphoinositide 3-kinase (PI3K) pathway, VAV1-mediated actin reorganization, and TCR downregulation. GRAIL-mediated ubiquitylation stabilizes expression of an inhibitor of the RHO family and has potent effects on T-cell activation. ITCH expression attenuates phospholipase Cγ1 (PLCγ1) activation by monoubiquitylation and targets the JUN family of transcription factors for degradation.As these E3 ubiquitin ligases contain disparate structural elements, subcellular localization and substrate targets, it is likely that they function at different levels of T-cell activation. Combining their effects together in an additive manner shunts T cells away from activation and towards T-cell anergy.