Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance

J Nedjic, M Aichinger, J Emmerich, N Mizushima… - Nature, 2008 - nature.com
J Nedjic, M Aichinger, J Emmerich, N Mizushima, L Klein
Nature, 2008nature.com
Recognition of self-antigen-derived epitopes presented by major histocompatibility complex
class II (MHC II) molecules on thymic epithelial cells (TECs) is critical for the generation of a
functional and self-tolerant CD4 T-cell repertoire. Whereas haematopoietic antigen-
presenting cells generate MHC-II–peptide complexes predominantly through the processing
of endocytosed polypeptides, it remains unknown if and how TECs use unconventional
pathways of antigen presentation. Here we address the role of macroautophagy, a process …
Abstract
Recognition of self-antigen-derived epitopes presented by major histocompatibility complex class II (MHC II) molecules on thymic epithelial cells (TECs) is critical for the generation of a functional and self-tolerant CD4 T-cell repertoire. Whereas haematopoietic antigen-presenting cells generate MHC-II–peptide complexes predominantly through the processing of endocytosed polypeptides, it remains unknown if and how TECs use unconventional pathways of antigen presentation. Here we address the role of macroautophagy, a process that has recently been shown to allow for endogenous MHC II loading,,,,, in T-cell repertoire selection in the mouse thymus. In contrast to most other tissues, TECs had a high constitutive level of autophagy. Genetic interference with autophagy specifically in TECs led to altered selection of certain MHC-II-restricted T-cell specificities and resulted in severe colitis and multi-organ inflammation. Our findings indicate that autophagy focuses the MHC-II–peptide repertoire of TECs on their intracellular milieu, which notably comprises a wide array of otherwise strictly ‘tissue-specific’ self antigens,. In doing so, it contributes to T-cell selection and is essential for the generation of a self-tolerant T-cell repertoire.
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