Abstract
In the present study, the relevance of EphB2 and EphB3 tyrosine kinase receptors for the maturation of medullary thymic epithelial cells (TECs) is analyzed. The absence of both molecules, but particularly that of EphB2, courses with altered maturation of medullary Cld3,4hiSSEA1+ epithelial progenitor cells, mature medulla epithelial cells, defined by the expression of specific cell markers, including UEA1, MHCII, CD40, CD80, and AIRE, and reduced expansion of medullary islets. In vivo assays demonstrate that these changes are a consequence of the absence of EphBs in both TECs and thymocytes. On the other hand, the changes, that remains in the adult thymus, correlated well with reduced proportions of E15.5 Vγ5+RANKL+ cells in EphB-deficient thymi that could result in decreased stimulation of RANK+ medullary TECs to mature, a fact that was confirmed by recovering of proportions of both CD40hiCD80+ and MHCIIhiUEA1+ mature medullary TECs of mutant E14.5 alymphoid thymic lobes by agonist anti-RANK antibody treatment. Accordingly, the effects of EphB deficiency on medullary TECs maturation are recovered by RANK stimulation.
Highlights
The thymus is a primary lymphoid organ morphological and functionally organized in two distinct histological compartments, the cortex and the medulla, whose origin and relationships remain obscure
We demonstrated that adult thymi of EphB2- and/or EphB3-deficient mice showed profound altera tions in both cortical and medullary epithelium that appear during thymus ontogeny [22,23,24], and recently, we confirmed a major role of EphB3 in governing the development of cortical thymic epithelium [25]
We first evaluated the development of thymic epithelial cells (TECs) by analyzing the expression of a cTEC marker, Ly51, and another medullary one, UEA1, in the total EpCAM+CD45− TECs in both wild type (WT) and EphBdeficient thymi at the last fetal stages (E15.5, E17.5), 7 days after birth (7PN) when the medulla begins its expansion [27], and in adults (6–8 weeks)
Summary
The thymus is a primary lymphoid organ morphological and functionally organized in two distinct histological compartments, the cortex and the medulla, whose origin and relationships remain obscure. The thymic primordium develops from the endoderm epithelium of the third pharyngeal pouch [3] which is later colonized by lymphoid progenitor (LP) cells coming from the fetal liver [4]. Differentiation of both cortical and medullary epithelium was explained according to a hierarchical model in which a common bipotent precursor cell was capable of giving rise to both cortical (c) thymic epithelial cells (TECs) and medullary (m) TECs [5]. Podoplanin+ mTEPCs of the cortico-medullary border have the potential to generate half of adult
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