Question

Describe the selection process of alpha/beta T cells and use the following words in your description: lymphotactin, prothymocyte, double negative thymocyte, double positive thymocyte, single positive thymocyte, cortex, medulla, Hassall's corpuscles, post capillary venule

Answer 1

Answer:

The recognition of self-peptides that are embedded in major histocompatibility complex (MHC) molecules on thymic antigen-presenting cells (APCs) is critical for determining the fate of developing αβ T cells. Somewhat paradoxically, recognition of self can elicit diametrically opposed outcomes. On one hand, it is essential for thymocyte survival and commitment to either the CD4⁺ or CD8⁺ T cell lineage (that is, for positive selection of thymocytes). On the other hand, recognition of self can be a death verdict for thymocytes, mediating the negative selection of these cells, or it can skew cells to alternative fates, such as regulatory T (T_Reg) cell differentiation.

The classical affinity model of thymocyte selection offers an attractive conceptual framework to resolve this apparent contradiction. However, it does not take into account the fact that positive and negative selection largely occur in discrete thymic microenvironments, namely the cortex and the medulla, respectively. Both compartments contain selection niches composed of different types of APCs, thereby providing microenvironments that orchestrate a spatial and temporal segregation of thymocyte selection.

At the peak of its productivity, the mouse thymus each day generates around fifty million CD4⁺CD8⁺double positive (DP) thymocytes that audition for selection¹. More than 90% of these precursors are subject to death by neglect, as they express ‘useless’ T cell receptors (TCRs) that do not mediate positive selection. Positive selection of ‘mainstream’ αβ T cells is contingent upon permissive interactions with a single APC type, namely cortical thymic epithelial cells (cTECs). For conceptual clarity, we will therefore restrict a more detailed discussion of antigen presentation in the cortex to cTECs and their role in positive selection, and will only briefly touch upon negative selection in the cortex at the end of this section.

cTECs are arranged in a three dimensional scaffold that supports intimate interactions with double negative (DN) and DP thymocytes. In addition, individual cTECs can form multi-cellular complexes that encompass up to 20 thymocytes and are referred to as thymic nurse cells (TNCs). TNC numbers are decreased in TCR-transgenic mice, possibly as a consequence of ‘facilitated’ transit of thymocytes through β-selection and positive selection. Thus, it seems that TNC formation is not essential for T cell development per se, but may result from lengthy ‘audition’ events that occur when only a small subset of DP thymocytes meets the positive selection criteria. Consistent with this, in non-TCR transgenic mice, TNCs were enriched in thymocytes harbouring secondary TCRα rearrangements. Whether such unusual selection niches are indeed required to promote thymocyte survival and/ or continued TCR rearrangements remains to be shown.