Hoover, A. | Search bioRxiv

bioRxiv2019

Factors that influence the thymic selection of CD8αα intraepithelial lymphocytes

Thymocytes bearing {beta} T cell receptors (TCR{beta}) with high affinity for self-peptide-MHC complexes undergo negative selection or are diverted to alternate T cell lineages, a process termed agonist selection. Among thymocytes bearing TCRs restricted to MHC class I, agonist selection can lead to the development of precursors that can home to the gut and give rise to CD8-expressing intraepithelial lymphocytes (CD8 IELs). The factors that influence the choice between negative selection versus CD8 IEL development remain largely unknown. Using a synchronized thymic tissue slice model that supports both negative selection and CD8IEL development, we show that the affinity threshold for CD8 IEL development is higher than for negative selection. We also investigate the impact of peptide presenting cells and cytokines, and the migration patterns associated with these alternative cell fates. Our data highlight the roles of TCR affinity and the thymic microenvironments on T cell fate.

immunology↗

bioRxiv2019

A role for phagocytosis in inducing cell death during thymocyte negative selection

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, we demonstrate that phagocytosis promotes negative selection, and that negative selection is more efficient when the phagocyte also presents the negative selecting peptide. Our findings support a two-step model for negative selection in which thymocytes initiate the death process following strong TCR signaling, but ultimately depend upon phagocytosis for their timely death. Thus, the phagocytic capability of cells that present self-peptides is a key determinant of thymocyte fate.

immunology↗