Figure 1.

Thymocyte migration through distinct thymic microenvironments occurs in an ordered fashion, enabling appropriate interactions with stromal cells. Thymocyte progenitors enter the thymus through vessels at the cortico-medullary junction (CMJ). ETPs (CD3⁻CD4⁻CD8⁻c-Kit⁺CD44⁺CD25⁻) integrate cTEC-derived signals in the cortex near the CMJ, which promote survival and T-lineage-commitment. DN2 (CD3⁻CD4⁻CD8⁻c-Kit⁺CD44⁺CD25⁺) thymocytes migrate into the mid-cortex, as they rearrange TCRβ chain genes. Subsequent DN3 (CD3⁻CD4⁻CD8⁻c-Kit⁻CD44⁻CD25⁺) thymocytes that pass the β-selection checkpoint proliferate at the sub-capsule, and differentiate through a DN4 (CD3⁻CD4⁻CD8⁻c-Kit⁻CD44⁻CD25⁻) stage to become DP (CD4⁺CD8⁺) thymocytes. DP cells, which rearrange TCRα chain genes, are localized throughout the cortex, with a bias toward the medulla. Interactions with cTECs induce positive selection of DP cells expressing TCRs with low avidity for self-peptide:MHCs. Auto-reactive DP thymocytes can be negatively selected in the cortex. Positively selected DP cells begin to migrate rapidly and enter the thymic medulla, guided by chemokine gradients, as they differentiate into SP thymocytes. SP cells rapidly scan mTECs and DCs during their 4–5-day residence time in the medulla to encounter a wide array of self-peptides, which induce auto-reactive cells to undergo apoptosis or diversion into the Treg lineage. Mature SP thymocytes egress from the thymus through blood vessels in the CMJ.