Aire (autoimmune regulator), the gene responsible for the clinical disorder autoimmune polyendocrinopathy syndrome type I, has recently been identified as an important mediator of central tolerance. Structural characteristics and biochemical data suggest that Aire might play a direct role in transcription and function as an ubiquitin ligase. Aire up-regulates the transcription of certain organ-specific self-antigens in medullary thymic epithelial cells (mTECs) and has a role in the negative selection of organ-specific thymocytes (Su and Anderson 2004). Aire promotes the tolerance of thymocytes by inducing the expression of a battery of peripheral-tissue antigens in mTECs. The mechanism whereby Aire exerts its tolerance-promoting function is not primarily positive selection of regulatory T cells but rather negative selection of T effector cells. Surprisingly, supplementing its influence on the transcription of genes encoding peripheral-tissue antigens, Aire somehow enhances the antigen-presentation capability of mTECs. Thus, this transcriptional control element promotes central tolerance both by furnishing a specific thymic stromal cell type with a repertoire of self-antigens and by better arming such cells to present these antigens to differentiating thymocytes. In Aire's absence, autoimmunity and ultimately overt autoimmune disease develops (Anderson et al. 2005).
At certain stages of male gametogenesis, a broad range of genes is expressed. The underlying mechanism and the biological significance of this phenomenon remain elusive. Derbinsky et al. inquired whether the spectrum of ectopically expressed genes is distinct or shared between mTECs and testis. They analyzed gene expression in cDNA libraries prepared either from whole testis or highly enriched immature gametocytes. Of 19 tissue-specific genes expressed in the thymus, 14 were also expressed in the testis. The transcription factors Whn and Aire, both of which have been ascribed specific roles in thymus biology, were also found in male game-tocytes. The authors suggested that this mechanism may facilitate tolerance induction to self-antigens that would otherwise be temporally or spatially secluded from the immune system.
Such spatially secluded antigens as cancer/testis (CT) antigens, of which more than 40 have now been identified, are encoded by genes normally expressed in the human germ line but are also expressed in melanoma and carcinomas of the bladder, lung, and liver. These immunogenic proteins are being vigorously pursued as targets for therapeutic cancer vaccines (Van Der Bruggen, Zhang, Chaux, Stroobant, Panichelli, Schultz, Chapiro, Van Den Eynde, Brasseur, and Boon 2002; Simpson, Caballero, Jungbluth, Chen, and Old 2005). It is very important that the array of promiscuously expressed self-antigens in mTECs includes well-known targets for cancer immunotherapy, such as a-fetoprotein, tyrosinase, and gp100. Therefore, intrathymic selection makes the immune system tolerant to tumor-associated antigens. Gene expression in normal tissues may result in tolerance of high-avidity CTL, leaving behind low-avidity CTL that cannot provide effective immunity against tumors expressing the relevant target antigens. Evidently, any antitumor vaccine targeted to tumor-associated antigens should be inefficient due to the loss of high-avidity T cell clones capable to be stimulated.
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