Maturational stage-dependent thymocyte responses to TCR engagement

Abstract

Thymocyte positive and negative selection are dependent on avidity-driven TCRmediated recognition events in the thymus. High-avidity recognition events result in negative selection, while low-avidity recognition events result in positive selection. However, it has not been established how thymocytes maturation stages affect their responses to TCR signals of different avidities. We gained insight into this question when we reduced thymocyte selection to an in vitro system, in which full maturation of developmentally synchronized immature double-positive thymocytes was induced on a cloned line of thymic epithelial cells. Our analysis of the kinetics of thymocyte development supports a multi-phasic model of thymic selection. In it, thymocyte maturation stages as well as interaction avidity control the outcome TCR stimulation. Positive selection is initiated during a primary recognition event that proceeds independently of the TCR avidity. During a secondary recognition event the final fate of thymocyte, full maturation versus negative selection, is determined by TCR avidity.

Negative selection of the T‐cell repertoire: where and when does it occur?

“…We observed that negative selection could take place in the absence of positive selection, when bone marrow‐derived thymocytes presented TCR ligands sufficient for negative but insufficient for positive selection in a thymus in which epithelial cells expressed allogeneic MHC ligands not suited for positive selection (30). These data are not compatible with views seeing positive selection as an event that must precede negative selection (31, 32). Hence, negative selection may remove cells with degenerate specificity prior to their positive selection, such that the repertoire is properly focused on class I and class II self‐MHC molecules (29).…”