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An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a

Abstract

Thymic positive selection is based on the interactions of T cell antigen receptors (TCRs) with self peptide–major histocompatibility complex (MHC) ligands, but the identity of selecting peptides for MHC class II–restricted TCRs and the functional consequences of this peptide specificity are not clear. Here we identify several endogenous self peptides that positively selected the MHC class II–restricted 5C.C7 TCR. The most potent of these also enhanced mature T cell activation, which supports the hypothesis that one function of positive selection is to produce T cells that can use particular self peptide–MHC complexes for activation and/or homeostasis. We also show that inhibiting the microRNA miR-181a resulted in maturation of T cells that overtly reacted toward these erstwhile positively selecting peptides. Therefore, miR-181a helps to guarantee the clonal deletion of particular moderate-affinity clones by modulating the TCR signaling threshold of thymocytes.

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Figure 1: Positive selection of 5C.C7 T cells by endogenous peptides.
Figure 2: An endogenous selecting peptide contributes to mature T cell activation.
Figure 3: Importance of miR-181a for T cell central tolerance.
Figure 4: Negative selection threshold set by miR-181a.
Figure 5: Thymocytes downregulate miR-181a in response to selection signals.

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Acknowledgements

We thank P. Allen (Washington University) for peptide sequence data and critical discussions; C.-Z. Chen for comments on the manuscript; D. Mathis and C. Benoist (Harvard University) for Ii-deficient mice; E.W. Newell and Y. Wong for help with cell sorting; and T. Mao for help with RNA blot analysis. Supported by the Howard Hughes Medical Institute (P.J.R.E. and M.M.D.), Duke University (Q.-J. L.) and the US National Institutes of Health (RO1 AIO22511).

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P.J.R.E., Q.-J.L. and M.M.D. conceived of the project, designed experiments and interpreted results; P.J.R.E. and Q.-J.L. did experiments and analyzed data; S.J. quantified miR-181a in terms of TCR signaling feedback and expression analysis for GP peptides; J.X. contributed critical reagents and technical support; and P.J.R.E., Q.-J.L. and M.M.D. prepared the manuscript.

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Correspondence to Qi-Jing Li or Mark M Davis.

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Q.-J.L. and M.M.D. are listed as inventors in a US patent application (11/977,506) entitled “Modulation of T cell signaling threshold and T cell sensitivity to antigens” that includes among its claims that miR181a functions in part to help prevent self-reactive T cells from emerging from the thymus.

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Ebert, P., Jiang, S., Xie, J. et al. An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a. Nat Immunol 10, 1162–1169 (2009). https://doi.org/10.1038/ni.1797

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