Among the vast T cell population in the thymus are some dendritic cells (DCs) that home to the medullary regions. Some studies have shown that these DCs can obtain self-peptides from medullary thymic epithelial cells (mTECs) and use them to negatively select T cells. However, since there is not yet a way to selectively delete thymic DCs experimentally, their definitive role remains a mystery. Equally puzzling is their developmental origin as some studies show they can migrate to the thymus from the periphery whereas others propose they come from early thymic progenitors. In 2012, Amanda Moore et al. in the lab of Dr. Michele Anderson showed that some early T cell subsets are transcriptionally primed for DC development and can ultimately become DCs.
It has been known for a long time that pro-T cells can give rise to thymic DCs both in vitro and upon adoptive transfer. However, in vitro conditions often use cytokines and factors that would not normally exist in the thymus and adoptive transfer experiments use either irradiation or cell numbers far greater than normal physiological conditions. By injecting wild type, non-irradiated mice with early T cell subsets (early thymic progenitors (ETPs), DN1d, DN1e), the authors showed that “DCs can arise in the thymus from early T cell progenitors in essentially natural conditions.” The use of completely unaltered conditions was a challenge, as the transferred cells have to compete for a niche with preexisting cells in the thymus. Initial attempts to characterize the phenotype of the transferred cells by flow cytometry failed due to the low number of cells. The authors took an alternative approach and, using microscopy, showed that some of the transferred cells acquired a CD11c phenotype and localized near mTECs in medullary regions of the thymus.
Two main types of DCs colonize the thymus, plasmacytoid DCs (pDCs) and classical (CD8+ and CD8-) DCs (cDCs), all of which are also present in the spleen (3). Despite the phenotypic similarities, Moore et al. showed that the expression of some transcription factors (PU.1, Spi-B, Id2) and Notch receptors vary within subtypes depending on their microenvironment. Importantly, thymic pDCs contained higher expression of Notch receptors than splenic pDCs, making them more transcriptionally similar to early T cell subsets. Notch signaling has been implicated as a negative regulator for development of some DC subsets, but can be required for others. Moore et al. showed that unlike other myeloid cells, in some cases DCs developed better under intermediate rather than low levels of Delta-like 1 and Delta-like 4, suggesting that the moderate levels of DL4 in the thymic medulla are permissive towards DC lineage.
Besides transcription factors and Notch receptors, thymic DCs also shared similar mRNA expression of CCR7 and CCR4 as some T cell progenitor subsets. Since both of these receptors are important for homing to medullary regions of the thymus, the authors proposed a model in which some early T cell subsets upregulate CCR4 and CCR7 expression and move towards the medulla where moderate levels of DL4 allow them to divert into the DC lineage.
Much more remains to be answered. Using a completely natural environment for DC development, although more physiologically relevant, is tedious and limiting. Therefore, Amanda Moore is currently optimizing experiments to try to detect the cells by flow cytometry using genetically modified mice. So far, IL-7R-knockout mice or mice receiving a low dose of radiation seem to be promising bone marrow recipients as their medullary regions, although lower in cellularity, are fairly intact. These assays will help them elucidate which DC subsets arise preferentially from specific DN1 progenitors. Further work on defining the developmental path of thymic DCs could hold crucial insights to their unresolved role in the thymus and their potential in inducing tolerance. After all, as we know from other lymphoid organs, without DCs T cells wouldn’t be able to function.
Mayra Cruz Tleugabulova
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