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I came across a recent article in science which described how certain type of cells within the thymus that express autoimmune regulators (AIRES) that act as safety net for eliminating autoreactive immune cells.


Science 8 August 2008:Vol. 321. no. 5890, pp. 776 - 777DOI: 10.1126/science.1162966
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Perspectives
IMMUNOLOGY:A Breath of Aire for the PeripheryBruno Kyewski*
The term "self-tolerance" encompasses all mechanisms that protect the body against attack by its own immune system. The adaptive arm of the immune system generates immune cells that express antigen-specific receptors by a random mechanism that requires quality control--selecting a "personalized" repertoire of receptors directed against foreign but not self-antigens (1). Central and peripheral tolerance to self are distinguished according to the site where tolerance is imposed (2). Central tolerance for T lymphocytes occurs in the thymus, where their primary antigen receptor repertoire is generated. Here, developing T cells that recognize and react to self-antigens are eliminated or diverted into T regulatory cells that suppress activation of the immune system and prevent self-reactivity. Although the thymus displays a vast array of self-antigens, including those whose expression is otherwise restricted to specific tissues, this collection is nevertheless incomplete. On page 843 of this issue, Gardner et al. (3) report how peripheral lymphoid tissues act as a safety net, preventing T cells specific for antigens not presented in the thymus from escaping elimination.
Medullary thymic epithelial cells, a particular thymic stromal cell type, express a diverse set of genes that are otherwise restricted to certain tissues and/or stages of development (4). This so-called promiscuous gene expression in the thymus is partly regulated by a transcriptional regulator called the Autoimmune regulator (Aire). Mice deficient in Aire develop a multi-organ autoimmune syndrome, similar to that of humans with functional mutations in the Aire gene (5).
Aire is highly expressed in thymic medullary epithelial cells. However, the functionally relevant expression of Aire in cells of peripheral lymphoid organs has been controversial (5-9). Gardner et al. now identify cells in peripheral lymph nodes, spleen, and Peyer's patches (lymphoid structures of the gut), that express Aire and mediate deletion of auto-reactive T cells. The authors genetically engineered mice in which the promoter of the Aire gene drives expression of a fusion protein composed of green fluorescent protein and islet-specific glucose-6-phosphatase related protein (Igrp), an antigen specific to the pancreas. Of the medullary thymic epithelial cells and peripheral cells that expressed the reporter protein, 85% and 25% expressed endogenous Aire, respectively. Most of these peripheral cells, called extrathymic Aire-expressing cells, were stromal-type epithelial cells, located at the interface between T and B cell areas in peripheral lymphoid tissues. These cells also expressed receptors characteristic of antigen-presenting cells, but differed in several markers from the medullary epithelial cells in the thymus. Surprisingly, some of these extrathymic Aire-expressing cells were highly mobile within the lymph node microenvironment, and at the same time were able to delete T cells specific for the reporter protein.
Complementary tolerance. The transcriptional regulator Aire controls the expression of complementary pools of self-antigens in the thymus and peripheral lymphoid tissues that sequentially imprint central and peripheral T cell tolerance, respectively.
CREDIT: C.BICKEL/SCIENCEPerhaps the most intriguing result of this study relates to the target genes controlled by Aire in the thymus versus the periphery. The number of genes in the latter is about one-tenth of that in the thymus, and their degree of Aire-dependent regulation is less pronounced. Moreover, although there is little overlap between the gene pools, both are clearly enriched in genes encoding for tissue-restricted self-antigens (see the figure). The distinct composition of both gene pools favors a role for peripheral tolerance that is complementary to tolerance developed in the thymus. A recent study by Lee et al. also identified a fraction of nonhematopoietic cells in mesenteric lymph nodes that express Aire and certain tissue-restricted self-antigens, and mediates peripheral T cell deletion (9). However, these cells were less rigorously enriched, and differed phenotypically, compared to those identified by Gardner et al. Moreover, the data of Lee et al. are more in line with the concept that peripheral tolerance serves as a backup for central tolerance rather than being complementary.
The study by Gardner et al. still leaves some important questions that need to be answered before a definitive role can be assigned to Aire in peripheral tolerance. Why do only 25% of peripheral cells in the transgenic mice that express the fluorescent reporter protein also express endogenous Aire? Is it due to ectopic expression of the reporter construct in otherwise Aire-negative cells? Is endogenous expression of Aire too low to be detected, or is expression of Aire and the reporter protein not synchronized? The relatively low concordance between the reporter and endogenous Aire expression may also contribute to the apparently relatively low degree of gene expression induced by Aire in the peripheral cells, which for most genes is less than twofold compared to the background expression in Aire-deficient mice.
Although tolerance induction is thought to be exquisitely sensitive to low numbers of self-antigens that are presented to T cells in the context of the major histocompatibility complex, it will be essential to show that the low expression level of endogenous tissue-restricted self-antigens in peripheral Aire-expressing cells are "tolerogenic." After all, at first glance, the autoimmune phenotype of Aire-deficient mice was fully reproduced by transplanting Aire-deficient thymic stromal cells (with no functional evidence for Aire in extrathymic sites) (5). Given the different composition of self-antigens displayed in peripheral cells, the autoimmune phenotype caused by lack of Aire in the periphery may have been subtle and previously overlooked. Notwithstanding these caveats, the study by Gardner et al. raises intriguing questions about the role and function of Aire and the nature of the peripheral cells that express this factor (10).
The emergence of the extrathymic Aire-expressing cells in vertebrates is interesting, given that organized secondary lymphoid organs evolved much later than the thymus (11). Aire is a single-copy gene with orthologs in mammals, birds, and fish whose structure has been conserved in vertebrates over more than 400 million years (12). No ancestral Aire genes have been reported in invertebrates. This suggests that Aire and its role in tolerance were acquired early during vertebrate evolution, most likely concurrent with the emergence of the adaptive immune system. One question is whether Aire's only role is to ensure central tolerance, or whether it has been coopted for other functions. The study by Gardner et al. now presents a strong argument in favor of the latter--Aire also seems to contribute to establishing peripheral tolerance.