Extrathymic Aire-Expressing Cells Are a Distinct Bone Marrow-Derived Population that Induce Functional Inactivation of CD4+ T Cells

Abstract

Summary The autoimmune regulator (AIRE) is essential for prevention of autoimmunity; its role is best understood in the thymus where it promotes self-tolerance through tissue-specific antigen (TSA) expression. Recently, extrathymic Aire-expressing cells (eTACs) have been described in murine secondary lymphoid organs, but the identity of such cells and their role in immune tolerance remains unclear. Here we have shown that eTACs are a discrete major histocompatibility complex class II (MHC II)hi, CD80lo, CD86lo, epithelial cell adhesion molecule (EpCAM)hi, CD45lo bone marrow-derived peripheral antigen presenting cell (APC) population. We also have demonstrated that eTACs can functionally inactivate CD4+ T cells through a mechanism that does not require regulatory T cells (Treg), and is resistant to innate inflammatory stimuli. Together these findings further define eTACs as a distinct tolerogenic cell population in secondary lymphoid organs.

Mendelian Genetics of Human Susceptibility to Fungal Infection

“…AIRE has recently been implicated in induction of peripheral tolerance; specifically, antigen-presenting extrathymic AIRE-expressing cells within secondary lymphoid organs can functionally inactivate CD4 þ T cells via regulatory T-cell-independent mechanisms (Gardner et al 2013). Not surprisingly, AIRE deficiency results in escape of selfreactive T cells in the periphery and development of self-reactive autoantibodies, which are both considered responsible for the autoimmune manifestations of the syndrome, principal of which are hypoparathyroidism and adrenal insufficiency (Ahonen et al 1990).…”

Expression and prognostic significance of the autoimmune regulator gene in breast cancer cells

“…11,12 Not only is AIRE highly expressed in mTECs, but there is evidence of AIRE expression in murine peripheral lymphoid organs. [13][14][15] The characteristics and functions of extra-thymic AIRE-expressing cells (eTACs) have recently been described; they are a CD45 low bone marrow-derived antigen-presenting population, mediating tolerance primarily by inducing inactivation of effectors cells through a mechanism involving deficient co-stimulation. 13 Very recently, AIRE expression was reported in human and mouse keratinocytes and in tumors originating in stratified and pseudostratified epithelia, as head and neck squamous carcinomas.…”

“…[13][14][15] The characteristics and functions of extra-thymic AIRE-expressing cells (eTACs) have recently been described; they are a CD45 low bone marrow-derived antigen-presenting population, mediating tolerance primarily by inducing inactivation of effectors cells through a mechanism involving deficient co-stimulation. 13 Very recently, AIRE expression was reported in human and mouse keratinocytes and in tumors originating in stratified and pseudostratified epithelia, as head and neck squamous carcinomas. 16,17 Thus, the shared feature of promiscuous expression of some genes by mTECs and cancer cells 18,19 raises the possibility that analogous mechanisms of transcriptional regulation operate in both cell types and that AIRE, as part of or a consequence of such mechanisms, is ectopically activated in some solid human tumors.…”

Induction de la tolérance centrale dans le thymus par le facteur de transcription Aire

“…Aire est en effet exprimé par un sous-type de cellules stromales dans les organes lymphoïdes secondaires. Il semblerait de plus avoir la capacité d'inactiver l'activité de lymphocytes CD4 + autoréactifs qui ont échappé au processus de sélection thymique [45]. ‡ SUMMARY Induction of central tolerance by the factor Aire: molecular and epigenetic regulation The establishment of thymic central tolerance is a critical process to prevent the development of autoimmune diseases.…”