Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self

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Abstract

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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Figure 1: OT-I T cells proliferate in GALT and the peripheral lymph nodes of iFABP-tOVA transgenic mice.
Figure 2: OT-I T cells encounter antigens in the peripheral lymph nodes of iFABP-tOVA transgenic mice.
Figure 3: CD8+ dendritic cells present OVA in MLNs but not peripheral lymph nodes.
Figure 4: Lymph node stromal cells express OVA in iFABP-tOVA transgenic mice.
Figure 5: Lymph node stromal cells activate naive OT-I T cells in iFABP-tOVA transgenic mice.
Figure 6: Peripheral-tissue antigens are expressed by lymph node stroma.
Figure 7: Lymph node stromal cells express Aire.
Figure 8: UEA-I+ lymph node cells express and present intestine-associated antigens.
Figure 9: Lymph node stromal cells induce deletion of OT-I T cells in iFABP-tOVA transgenic mice.

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Acknowledgements

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.).

Author information

J.-W.L. and S.J.T. contributed to every aspect of this manuscript (experimentation, mouse work, writing and figure composition); S.J.T. provided most of the funding; M.E. did the cell trafficking experiments; J.S. did the in vitro presentation assays with purified IECs; J.E.B. did the immunoblots; A.C.C. and A.Y. helped with immunofluorescence staining of tissue sections; and J.K.H. contributed reagents and guidance on experiments involving the A33 antigen.

Correspondence to Shannon J Turley.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

T cell proliferation in peripheral lymphoid tissues is not due to the direct presentation of OVA antigen by IECs. (PDF 2641 kb)

Supplementary Fig. 2

Analysis of bone marrow chimerism. (PDF 712 kb)

Supplementary Fig. 3

Analysis of A33 antigen expression in parenchymal tissues by fluorescence microscopy. (PDF 153 kb)

Supplementary Table 1

Primer sequences. (PDF 646 kb)

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