Following positive selection, CD4 or CD8 is downregulated, yielding CD8+ or CD4+ single positive (SP) thymocytes, which are found in the thymic medulla.  If a strong signal through the TCR is transduced within the medulla, the thymocyte undergoes apoptosis, thus preventing maturation of auto-reactive T cells. This selective process of culling autoreactive thymocytes is termed “negative selection”.

Given that thymocytes at discrete developmental stages are localized in distinct regions of the thymus, it is likely that they receive region-specific signals in different thymic microenvironments. These signals may come in the form of cell:cell interactions or soluble cues. Our lab is interested in elucidating the molecular and cellular signals that guide thymocytes between thymic microenvironments, and promote thymocyte:stromal cell crosstalk interactions to ensure proper T cell development.

The thymus is not uniform in structure, but rather is organized into two lobes, each with a central medulla, surrounded by cortex.

Thymocyte progenitors (DN1) enter the thymus through vasculature at the cortico-medullary junction. They then initiate rearrangements of the beta chain gene segments encoding one chain of their antigen receptor, the T cell receptor (TCR). The precursors undergoing such rearrangements (DN2) are located further in the central cortex. Thymocytes that successfully rearrange TCRβ chain genes proliferate near the thymic capsule (DN3- DN4).

Subsequently, CD4 and CD8 co-receptors are upregulated, resulting in double positive (DP) thymocytes, which are found throughout the cortex. If DPs successfully rearrange TCRα chain genes, the TCRαβ heterodimer is expressed. This antigen receptor can the be signaled by self-antigens within the thymic environment. Only those thymocytes with functional TCRs that are triggered by antigens in the cortex survive. This selective survival is termed “positive selection”.