Thymus medulla under construction: Time and space oddities

Abstract

Within the thymus, thymic epithelial cells (TECs) span along the outer cortex and inner medulla to form specialized niches capable of generating T cells, which are simultaneously reactive to pathogens and tolerant to one's own organs. To solve the conundrum imposed by the random assortment of αβ T-cell receptors (TCR), TECs select T cells with a broad range of reactivity against foreign antigens, while generally controlling the fate of selfreactive ones. Cortical TEC (cTEC) and medullary TEC (mTEC) sublineages constitute the two main stromal components of the preinvoluted thymus (reviewed in [1]). While cTECs promote Correspondence: Dr. Nuno L. Alves e-mail: nalves@ibmc.up.pt T-cell lineage commitment and positive selection, mTECs regulate the elimination of autoreactive T cells and the differentiation of regulatory T cells (reviewed in [2]). The particular relevance of mTECs to tolerance induction is illustrated by studies in mice and humans showing a direct link between genetic defects in mTEC differentiation and the development of autoimmunity (reviewed in [1]). Intrinsic to the role of mTECs is their capacity to express tissue-restricted antigens (TRAs), a process that depends in part on autoimmune regulator (Aire) and the recently described Fezf2 [3,4]. These two transcription factors control the expression of highly diverse and complementary TRAs in mTECs [3,4], so that the coverage of virtually all self-antigens is organized in random patterns of gene expression in just a few hundred mTECs [3,5,6]. This seemingly stochastic process secures the repeated Immunol. 2016. 46: 829-833 representation of the entire genome to developing T cells within the thymic medulla. In this regard, understanding the foundation of the mTEC microenvironment is important to comprehend how the thymus establishes the limits of tolerance to peripheral tissues. The identification of bipotent TEC progenitors (TEPs) in both the embryonic [7] and postnatal [8] thymus provided evidence that mTECs and cTECs share a common origin. The initial descriptions of mTEC precursors (mTEPs) [9][10][11] led to the notion that mTECs undergo a diversification route unrelated from cTECs. Nonetheless, the blueprint of TEC development became more complex with the observations that embryonic TEPs expressing cortical markers can generate both cTECs and mTECs [12][13][14]. These findings support a refined model whereby progenitors transverse through the cortical lineage prior to commitment to mTEC differentiation in the embryonic thymus (reviewed in [15]). Still, we lack critical information on the nature of TEPs as well as on their functional contribution to the maintenance of thymic epithelial niches across life. Another area of uncertainty deals with the molecular networks that underlie the precursor-product relationship between TEPs, lineage-restricted precursors, and mature TEC subsets. Research in TEC progenitors has been under intense scrutiny in the past years, regularly providing new advances to our understanding of thymic biology. In this iss...

Dissecting and modeling the emergent murine TEC compartment during ontogeny

“…Data from experimental ex vivo analysis and Re‐aggregate Thymic Organ Culture (RTOC) reconstitution assays combined with mathematical modeling support the following developmental sequence: MHCII − CD80 − → MHCII lo CD80 − → MHCII hi CD80 − → MHCII hi CD80 hi TECs, whereby MHCII hi CD80 − and MHCII hi CD80 hi TECs bear features of cTECs and mTECs respectively. These emergent MHCII hi CD80 − cTECs directly generate mature mTECs in vivo and in vitro thus, supporting the asynchronous model of TEC lineage commitment .…”

“…Several recent studies focused on identifying the bipotent TEC progenitor/stem cells and mTEC/cTEC‐ lineage‐restricted precursors. To this end a number of markers and lineage tracing models have been used . Here, we sought to follow embryonic TEC development in wild‐type BL6 mice in an “unbiased” way, focusing on the complete TEC compartment using markers namely EpCAM, MHCII and CD80 on living, non‐hematopoietic (CD45 − ) thymic stroma.…”

“…This would entail down‐regulation of cTEC markers concomitant with upregulation of markers specifying the early mTEC lineage. In this scheme cTEC commitment would thus represent the default pathway . Thus, it has been shown that perinatal TEC progenitors expressing cortical markers (namely CD205, Ly51, β5t, IL7, CCRL1) harbor the potential to give rise to differentiated cTECs and mTECs and these progenitors traverse through a cTEC‐like stage prior to commitment into mTECs.…”

Setting Up the Perimeter of Tolerance: Insights into mTEC Physiology

“…The development of mTECs commences during organogenesis and continues during adulthood. In recent years the identification of distinct subtypes of mTEC precursors, such as Claudin3,4 + stage-specific embryonic antigen (SSEA) + , Claudin3,4 + , receptor activator of NF-κB (RANK) + , and podoplanin + cells, has emphasized the dynamics of this process [4]. NF-κB signaling is critical to mTEC differentiation and is triggered by the engagement of members of the TNF receptor superfamily (TNFRSF) -RANK, CD40, and LTβR -by their ligands expressed in developing thymocytes [1].…”

“…TEC progenitor' stage that expresses phenotypic and molecular traits associated with cortical TEC (cTEC) precursors (cTEPs) before the commitment to a cTEC or mTEC fate [2]. The NF-кB pathway regulates various stages of their differentiation, from mTEC progenitors (mTEPs) to immature (Imm) and mature (Mat) mTECs [4]. While p53 [5] and STAT3 [11,12] appear to control the maintenance of the broad mTEC compartment, IFN regulatory factor (IRF) 4 [7] and IRF7 [8] seem to regulate the immature-mature mTEC transition.…”