The intestinal epithelium functions to absorb nutrients and to protect the organism against microbes. To prevent autoimmune attack on this vital tissue, T cell tolerance to intestinal self-antigens must be established. Central tolerance mechanisms involve medullary thymic epithelial cells (mTECs), which use endogenously expressed peripheral-tissue antigens (PTAs) to delete self-reactive thymocytes. The prevailing model for the induction of peripheral tolerance involves cross-presentation of tissue antigens by quiescent dendritic cells. Here we show that lymph node stromal cells present endogenously expressed PTAs to T cells. Moreover, antigen presentation by lymph node stroma is sufficient to induce primary activation and subsequent tolerance among CD8+ T cells. Thus, lymph node stromal cells are functionally akin to mTECs and provide a direct strategy for purging the peripheral repertoire of self-reactive T cells.
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We thank M. Nussenzweig (Rockefeller University) and L. Lefrancois (University of Connecticut) for the gifts of CD11c-EYFP transgenic mice and iFABP-tOVA transgenic mice, respectively; W. Heath, G. Losyev, K. Irving, A. Bellemare-Pelletier and M. Werneck for technical advice or support; and C. Benoist, K. Wucherpfennig and A. Goldrath for critically reading the manuscript. Supported by the Claudia Adams Barr Program for Innovative Cancer Research, the Diabetes and Endocrinology Research Center of the National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK36836-19 to S.J.T.) and the Institut National de la Recherche Agronomique (M.E.).
The authors declare no competing financial interests.
T cell proliferation in peripheral lymphoid tissues is not due to the direct presentation of OVA antigen by IECs. (PDF 2641 kb)
Analysis of bone marrow chimerism. (PDF 712 kb)
Analysis of A33 antigen expression in parenchymal tissues by fluorescence microscopy. (PDF 153 kb)
Primer sequences. (PDF 646 kb)
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