Thymic DCs improve their tolerance

A new study in Nature describes a role for medullary dendritic cells (DCs) in the positive selection of CD4⁺CD25⁺ regulatory T (T_Reg) cells in the thymus. This complicates the traditional view of central tolerance, in which epithelial cells in the cortex mediate positive selection of developing thymocytes, whereas DCs in the medulla mediate negative selection. The latter process ensures lack of reactivity to self-MHC plus self-peptide; now, this is joined by the positive selection of T_Reg cells as another central-tolerance mechanism mediated by DCs that prevents reactivity to self in the periphery.

Yong-Jun Liu and colleagues showed that human Hassall's corpuscles — which are groups of epithelial cells in the thymic medulla — express the interleukin-7-related cytokine thymic stromal lymphopoietin (TSLP). TSLP-expressing Hassall's corpuscles were colocalized with CD11c⁺DC lysosomal-associated membrane protein (DC-LAMP)⁺ DCs, with DC-LAMP being a marker of mature, activated DCs. In in vitro experiments, TSLP induced peripheral-blood and thymic CD11c⁺ immature DCs to upregulate expression of DC-LAMP and other markers of maturation and activation, such as CD80, CD86 and MHC class II molecules. The authors therefore propose that Hassall's corpuscles express TSLP to activate immature DCs in the thymus.

DCs that are activated with TSLP (denoted TSLP-DCs) induced the proliferation of CD4⁺CD8⁻ thymocytes but not other thymocyte populations, in vitro, and resulted in a tenfold increase in the number of CD25⁺ cells in this subset. This was a consequence of the proliferation of CD4⁺CD25⁻ cells and their differentiation into CD4⁺CD25⁺ cells, rather than of the proliferation of pre-existing CD4⁺CD25⁺ cells. The CD4⁺CD25⁺ cells that were induced by TSLP-DCs expressed Foxp3 (forkhead box P3) mRNA and inhibited the proliferation of CD4⁺CD25⁻ thymocytes stimulated with CD3- and CD28-specific antibodies, showing that they have the characteristics of classical T_Reg cells. T_Reg cells in the thymus were shown to be present only in the medulla in close proximity to DC-LAMP⁺ DCs and Hassall's corpuscles.

This new role for thymic DCs — after activation by TSLP produced by epithelial cells in Hassall's corpuscles — in the positive selection of T_Reg cells indicates another way in which DCs are involved in ensuring self-tolerance, by converting high-affinity autoreactive thymocytes into T_Reg cells rather than deleting them.