Autoreactive thymocytes are eliminated during negative selection in the thymus, a process important for establishing self-tolerance. Thymic phagocytes serve to remove dead thymocytes, but whether they play additional roles during negative selection remains unclear. Here, using a murine thymic slice model in which thymocytes undergo negative selection in situ, we demonstrate that phagocytosis promotes negative selection, and provide evidence for the escape of autoreactive CD8 T cells to the periphery when phagocytosis in the thymus is impaired. We also show that negative selection is more efficient when the phagocyte also presents the negative selecting peptide. Our findings support a model for negative selection in which the death process initiated following strong TCR signaling is facilitated by phagocytosis. Thus, the phagocytic capability of cells that present self-peptides is a key determinant of thymocyte fate.
Data that support the findings of this study are reported in figures accompanying the main text and supplementary figures.
- Ellen A Robey
- Nadia S Kurd
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All mice were bred and maintained under pathogen-free conditions in an American Association of Laboratory Animal Care-approved facility at the University of California, Berkeley. All procedures were approved by the University of California, Berkeley Animal Use and Care Committee under Animal Use Protocol #AUP-2016-07-9006-1.
- Shimon Sakaguchi, Osaka University, Japan
© 2019, Kurd et al.
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