Can a Proper T-Cell Development Occur in an Altered Thymic Epithelium? Lessons From EphB-Deficient Thymi

Abstract

For a long time, the effects of distinct Eph tyrosine kinase receptors and their ligands, ephrins on the structure, immunophenotype, and development of thymus and their main cell components, thymocytes (T) and thymic epithelial cells (TECs), have been studied. In recent years, the thymic phenotype of mutant mice deficient in several Ephs and ephrins B has been determined. Remarkably, thymic stroma in these animals exhibits important defects that appear early in ontogeny but little alterations in the proportions of distinct lymphoid cell populations. In the present manuscript, we summarize and extend these results discussing possible mechanisms governing phenotypical and functional thymocyte maturation in an absence of the critical T–TEC interactions, concluding that some signaling mediated by key molecules, such as MHCII, CD80, β5t, Aire, etc. could be sufficient to enable a proper maturation of thymocytes, independently of morphological alterations affecting thymic epithelium.

Intrathymic Selection and Defects in the Thymic Epithelial Cell Development

“…In general terms, the evidence supports that proper TEC-thymocyte interactions are a requisite for an adequate functional education of thymocytes and for the generation of a proper TCR repertoire. However, we [ 98 ] and other authors [ 82 , 99 , 100 , 101 ] have observed studying different experimental models that thymuses showing profound epithelial alterations maintain normal proportions of thymocyte subsets, including positive and negative selected thymocytes, and Treg cells.…”

“…EphB-deficient thymuses, although specific in their phenotypes, show some common features, such as hypocellularity, importantly altered epithelium but few changes in the proportions of thymocyte subsets. In addition, the mutant phenotype becomes evident early in the development but gradually increases in correlation with the establishment of TEC-thymocyte interactions [ 98 , 103 ].…”

“…Despite the important alterations undergone by the epithelial component, the EphB-deficient thymi show little changes in the thymocyte phenotype. Although, as mentioned above, reduced percentages of lymphoid progenitor cells seed the mutant thymi, there are no significant changes in the percentages of distinct thymocyte subsets subsequently [ 98 ], except for a slight increase of DN1 (CD4 − CD8 − CD44 + CD25 − )cell proportions and reduced DN3 thymocytes [ 107 , 108 ], and increased proportions of Vβ3CD4 + cells that suggest certain altered thymocyte selection. On the contrary, there were no differences between mutant and WT thymuses in the proportions of neither positive selected thymocytes or negative selected cells, nor in the percentage of total thymic Treg cells.…”

“…On the contrary, there were no differences between mutant and WT thymuses in the proportions of neither positive selected thymocytes or negative selected cells, nor in the percentage of total thymic Treg cells. In addition, in the periphery no changes occur in the proportions of Th1, Th2, and Th17 [ 98 ], and the percentage of Treg remains unchanged in the spleen but increases slightly in mutant inguinal lymph nodes (ILNs), as compared with WT values [ 98 ]. These results have been recently confirmed ( Figure 2 and Figure 3 ).…”

“…The so-called thymic nurse complexes (TNC), where single cTECs intimately interact with 5–30 thymocytes governing their secondary TCRα chain rearrangements, are a good experimental model to analyze the thymocyte–TEC interactions occurring in the thymic cortex [ 132 ]. Recently, we demonstrated that TNCs derived from EphB-deficient thymuses yielded fewer complexes due to the reduction of the numbers of TNCs containing 6–10 thymocytes, the most frequent in WT thymuses, but there were no changes in the proportions of positive selected TCRαβ hi CD69 + thymocytes [ 98 ]. In addition, the number and establishment of cell conjugates between TECs and DP thymocytes are altered when established with mutant DP cells [ 133 ].…”