Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance

Abstract

To investigate the role of Aire in thymic selection, we examined the cellular requirements for generation of ovalbumin (OVA)-specific CD4 and CD8 T cells in mice expressing OVA under the control of the rat insulin promoter. Aire deficiency reduced the number of mature singlepositive OVA-specific CD4 ؉ or CD8 ؉ T cells in the thymus, independent of OVA expression. Importantly, it also contributed in 2 ways to OVA-dependent negative selection depending on the Tcell type. Aire-dependent negative selection of OVA-specific CD8 T cells correlated with Aire-regulated expression of OVA. By contrast, for OVA-specific CD4 T cells, Aire affected tolerance induction by a mechanism that operated independent of the level of OVA expression, controlling access of antigen presenting cells to medullary thymic epithelial cell (mTEC)-expressed OVA. This study supports the view that one mechanism by which Aire controls thymic negative selection is by regulating the indirect presentation of mTEC-derived antigens by thymic dendritic cells. It also indicates that mTECs can mediate tolerance by direct presentation of Aire-regulated antigens to both CD4 and CD8 T cells. (Blood. 2011;118(9): 2462-2472) IntroductionFor many years investigators noted the ectopic expression of tissue-specific antigens (TSAs) in the thymus of normal and transgenic mice 1,2 and other species. 3,4 Although this observation was a fascinating one, the true impact of thymic expression of TSAs was not fully appreciated until the generation and analysis of Aire-deficient mice. [5][6][7] These studies were prompted by the discovery of a recessive autoimmune disease in humans referred to as autoimmune polyglandular syndrome type I or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. 8,9 This disease is associated with circulating tissue-specific autoantibodies that contribute to the destruction of target organs, mainly endocrine glands. [10][11][12] The first symptoms that typically appear during early childhood include chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenocortical failure. In adulthood, patients develop endocrine autoimmune diseases, such as gonadal atrophy, type 1 diabetes, hypothyroidism, and hepatitis. In addition, several ectodermic diseases may arise. 10 This disease was mapped to the AIRE locus, where several mutations have now been reported. 13 The generation of Airedeficient mice revealed 2 important observations: first, that many TSAs shown to have ectopic thymic expression were regulated by Aire and, second, that mice deficient in Aire were prone to autoimmune disease. 14 The initial report by Anderson et al 5 suggested that Aire controlled self-tolerance by enabling ectopic expression of TSAs in the medullary thymic epithelial cells (mTECs), although not all TSA genes appeared to be controlled by Aire. The ability of Aire to control thymic tolerance by regulating expression of TSAs was formally demonstrated by use of the RIP-HEL transgenic system, where the model antigen hen egg lysozyme (HEL) was expressed...

Elevated Mcl-1 inhibits thymocyte apoptosis and alters thymic selection

“…In accord with previous reports, 31,32 almost all Vb5/Va2 hi CD8SP thymocytes were deleted under the negative selecting conditions of OT-I BM/RIP-mOVA þ chimeras (Figures 5a, c and d). Expression of the BCL-2 transgene enabled more Vb5/Va2 hi thymocytes to escape deletion than expression of the Mcl-1 transgene did (Figure 5d, right panel).…”

“…31,32 Both Mcl-1 and BCL-2 overexpression increased positively selected OT-I thymocytes to a similar extent, although Mcl-1 favoured modest expansion of OT-I CD8SP with high levels of TCR. Whether this proportional increase (consistent with data from the H-Y system) reflects an effect of Mcl-1 overexpression on DP precursors or is intrinsic to the CD8SP compartment might be addressed by conditional overexpression following positive selection.…”

“…This transgene drives expression of OVA in the pancreas and kidney but also in epithelial cells of the thymic medulla, where its expression and/or presentation requires Aire. 31,32 When suggesting that mature thymocytes arose or accumulated more frequently within this subset.…”

Ovarian autoimmune disease: clinical concepts and animal models

“…88 A second possible outcome is that AIRE-expressing cells undergo apoptosis and are phagocytosed, along with their promiscuously expressed antigens, by resident thymic dendritic cells; the antigens are in turn crosspresented by the dendritic cells in the context of major histocompatibility complex class II, to developing CD4 1 cells. 89 Developing thymocytes that have successfully but randomly rearranged their T-cell receptors in the thymic cortex enter the medulla; should they efficiently recognize self-antigen presented by either mTEC or dendritic cells, they are eliminated and thus blocked from entering the periphery. On the other hand, lack of AIRE function due to genetic deletion or mutation prevents promiscuous gene expression, prevents the negative selection/deletion of autoreactive CD4 1 and CD8 1 T cells that recognize dominant, high affinity epitopes.…”

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

“…[27][28][29] Thymic DCs cross-present tissue-specific antigens expressed by mTECs. 30,31 Moreover, peripheral DCs migrate to the thymus where they present peripheral antigens. 32,33 Taken together, these observations suggest that DCs participate in the maturation of T cells and the generation of FoxP3 þ Tregs in the thymus.…”