Figure 2. Protein ubiquitylation in T-cell tolerance.

a | Autoimmune regulator (AIRE), a RING (really interesting new gene)-type E3 ligase, is implicated in expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (mTECs), which present antigens (including TSAs) to developing thymocytes to induce central tolerance to those antigens. In developing thymocytes, signalling through the T-cell receptor (TCR) causes negative selection by inducing thymocyte apoptosis through expression of NUR77 and BIM (B-cell-lymphoma-2-interacting mediator of cell death). The E3 ligase CBL (Casitas B-lineage lymphoma) can function as an E3 ligase for BIM. b | In mature peripheral T cells, ligation of the TCR in the absence of the appropriate co-stimulatory signals results in augmented expression of three E3 ligases — CBL-B, ITCH (itchy) and GRAIL (gene related to anergy in lymphocytes) — and this promotes the conjugation of ubiquitin to phospholipase C-γ1 (PLC-γ1) and protein kinase C-θ (PKC-θ), leading to the induction of T-cell anergy. This pathway seems to define at least one crucial state of T-cell anergy. Another RING-type E3 ligase, roquin, has been implicated in regulating the stability and/or translation of mRNA encoding inducible T-cell co-stimulator (ICOS) and interleukin-21 (IL-21). APC, antigen-presenting cell; Ca²⁺, calcium ions.