EphB receptors, mainly EphB3, contribute to the proper development of cortical thymic epithelial cells

Abstract

EphB and their ligands ephrin-B are an important family of protein tyrosine kinase receptors involved in thymocyte-thymic epithelial cell interactions known to be key for the maturation of both thymic cell components. In the present study, we have analyzed the maturation of cortical thymic epithelium in EphB-deficient thymuses evaluating the relative relevance of EphB2 and EphB3 in the process. Results support a relationship between the epithelial hypocellularity of mutant thymuses and altered development of thymocytes, lower proportions of cycling thymic epithelial cells and increased epithelial cell apoptosis. Together, these factors induce delayed development of mutant cortical TECs, defined by the expression of different cell markers, i.e. Ly51, CD205, MHCII, CD40 and β5t. Furthermore, although both EphB2 and EphB3 are necessary for cortical thymic epithelial maturation, the relevance of EphB3 is greater since EphB3-/- thymic cortex exhibits a more severe phenotype than that of EphB2-deficient thymuses.

Thymus aging in mice deficient in either EphB2 or EphB3, two master regulators of thymic epithelium development

“…Furthermore, the reduction of both areas is more important in the mutant thymuses, especially in the case of the cortex, supporting the occurrence of a more severe phenotype in aged EphB‐deficient mice than in the WT ones. Remarkably, the absence of EphB courses with altered morphology of cTECs exhibiting shortened or total absence of cell processes, 19,37,42 a feature proposed as mentioned above for explaining the role of thymic epithelium in thymus aging 63 . In fact, these premature changes in adult EphB‐deficient thymuses remain and increase along the lifetime as is evidenced in the current results.…”

“…On the contrary, in EphB‐deficient mice, the reduction of thymic cell content is more gradual and there is not an early decrease as the one found in WT thymuses, although, except at 24 months, mutant cellularity is lower than that of WT thymuses. Nevertheless, it is important to remark that embryonic and adult mutant thymuses already show a severe hypocellularity related with increased apoptosis and reduced cell proliferation in both developing thymocytes 18 and TECs 37,38 not occurring in WT thymuses.…”

“…Indeed, there are numerous differences between EphB2‐ and EphB3‐deficient thymuses, 17 including T‐cell differentiation 40 and lymphoid precursor cell seeding 26,41 . In addition, although both EphB2 and EphB3 are necessary for a proper development of the thymic epithelium, the lack of EphB2 largely affects the thymic medulla, 42 whereas the cortex is more importantly altered in EphB3 −/− thymuses 37 …”

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

“…Low numbers of recent emigrants seeding the mutant thymi and their slow maturation ( 10 , 15 ) are a major cause of the thymic hypocellularity, in addition to their increased apoptosis and reduced proportions of cycling thymocytes ( 9 ). Reduced proportions of cycling thymocytes could be associated with decreased Delta-like 4 (Dll4) and IL7 receptor α chain transcript ( 12 ) as is also observed in thymocytes exhibiting specific deletion of ephrin-B1 and ephrin-B2 ( 16 ), both molecules involved in the maturation of developing double-negative (DN) thymocytes ( 17 , 18 ).…”

“…The lack of Eph or ephrins courses with thymic hypocellularity that affect both thymocytes ( 9 , 10 ) and TECs ( 11 , 12 ), and the blockade of Eph/ephrin signaling reduces thymic cell numbers ( 13 , 14 ).…”