Immunology Select

The ability to distinguish self from nonself is crucial for proper immune system function, and disruption of self-tolerance can lead to the development of autoimmune disease. This Immunology Select highlights recent studies that uncover new mechanisms for inducing self-tolerance and provides insights into how self-tolerance breaks down in disease. To circumvent the inevitable problem that some developing T cells possess affinity for self-antigens, immature T cells are subjected to negative selection in the thymus. A new player in the process of thymic selection—autophagy—is described in a recent paper by Nedjic et al. (2008). Although autophagy (degradation of the cell's own components through the lysosomal pathway) is usually observed during periods of nutrient limitation, the authors find that autophagy in the thymus is permanently elevated. During thymic selection, self-antigens are presented to T cells by major histocompatibility (MHC) molecules on thymic epithelial cells. T cells that harbor receptors with high affinities for presented self-antigens are eliminated by apoptosis. The authors now provide evidence suggesting that autophagy may contribute to the processing and loading of endogenous self-antigens onto MHC class II molecules expressed by thy-mic epithelial cells. To ascertain the importance of autophagy in thymic selection, the authors examined mice lacking Atg5, a gene encoding an essential component of autophagosome formation. The authors predicted that as a result of Atg5 deficiency, the MHC class II-ligand repertoire against which autoreactive CD4 T cells are selected might be limited both in terms of the variety and the abundance of MHC ligands. Such a limited MHC-ligand repertoire would be likely to decrease the effectiveness of thymic selection, allowing more autoreactive T cells to escape elimination. Nedjic et al. show that this is indeed the case in a transplant mouse model. Athymic mice implanted with thymus tissue from mice lacking Atg5 develop autoimmune pathology characterized by inflammation of the gut (colitis) and other organs indicative of aberrant thymic selection and a breakdown in self-tolerance. Future work should examine whether a defect in autophagy contributes to autoimmunity in humans, a possibility raised by the recent discovery that the human autophagy gene ATG16L1 is part of a susceptibility locus for the inflammatory gut disorder Crohn's disease. To facilitate negative selection of T cells against self-antigens in the thymus, medullary thymic epithelial cells express genes not normally expressed in thymic tissue under the control of the transcriptional regulator Aire (autoimmune regulator). Gardner et al. (2008) now make the striking …