Insights into immune tolerance from AIRE deficiency

Abstract

AIRE is a well-established master regulator of central tolerance. It plays an essential role in driving expression of tissue-specific antigens in the thymus and shaping the development of positively selected T-cells. Humans and mice with compromised or absent AIRE function have markedly variable phenotypes that include a range of autoimmune manifestations. Recent evidence suggests that this variability stems from cooperation of autoimmune susceptibilities involving both central and peripheral tolerance checkpoints. Here we discuss the broadening understanding of the factors that influence Aire expression, modify AIRE function, and the impact and intersection of AIRE with peripheral immunity. This rapidly expanding body of knowledge will force a reexamination of the definition and clinical management of APS-1 patients as well as provide a foundation for the development of immunomodulatory strategies targeting central tolerance.

Figure 1. Defects in Aire cooperate with defects in peripheral tolerance to promote autoimmunity

Aire induces expression of TSAs in thymic mTECs, which are presented to developing single positive (SP) T cells. Self-reactive T cells that bind peptide-MHC complexes with high affinity are either deleted by negative selection or become thymically derived natural tTregs. Mutations in the Aire gene leading to reduced or absent AIRE function result in decreased TSA presentation and survival and thymic escape of autoreactive T-cell clones as well as a loss of tTreg induction. Autoreactive T-cells can then encounter cognate self-antigen presented by APCs in secondary lymphoid organs or peripheral tissues. When peripheral tolerance checkpoints are intact, autoreactive T cells are suppressed by inhibitory signals from Tregs as well as resting APCs. Failure of peripheral tolerance leads to their activation and autoimmune attack. RANKL and TGFβ are two factors known to influence mTEC function, and thereby, AIRE and TSAs expression. Therapies directly targeting these molecules or their downstream pathways may provide therapeutic opportunities for immune modulation in the context of hyperactivity or release of tolerance in the context of neoplastic transformation and cancer immunotherapy.