Lymphotoxin β Receptor Regulates the Development of CCL21-Expressing Subset of Postnatal Medullary Thymic Epithelial Cells

Abstract

Medullary thymic epithelial cells (mTECs) play a pivotal role in the establishment of self-tolerance in T cells by ectopically expressing various tissue-restricted self-Ags and by chemoattracting developing thymocytes. The nuclear protein Aire expressed by mTECs contributes to the promiscuous expression of self-Ags, whereas CCR7-ligand (CCR7L) chemokines expressed by mTECs are responsible for the attraction of positively selected thymocytes. It is known that lymphotoxin signals from the positively selected thymocytes preferentially promote the expression of CCR7L rather than Aire in postnatal mTECs. However, it is unknown how lymphotoxin signals differentially regulate the expression of CCR7L and Aire in mTECs and whether CCR7L-expressing mTECs and Aire-expressing mTECs are distinct populations. In this study, we show that the majority of postnatal mTECs that express CCL21, a CCR7L chemokine, represent an mTEC subpopulation distinct from the Aire-expressing mTEC subpopulation. Interestingly, the development of CCL21-expressing mTECs, but not Aire-expressing mTECs, is impaired in mice deficient in the lymphotoxin β receptor. These results indicate that postnatal mTECs consist of heterogeneous subsets that differ in the expression of CCL21 and Aire, and that lymphotoxin β receptor regulates the development of the CCL21-expressing subset rather than the Aire-expressing subset of postnatal mTECs.

T cell progenitor therapy–facilitated thymopoiesis depends upon thymic input and continued thymic microenvironment interaction

“…Presumably this would facilitate more interactions between the proTs and mTECs. This crosstalk provides important stimulatory signals for mTECs, which turn over every 10 to 14 days (47,48), through receptor activator of NF-κB, RANKL, CD80/86, LTβR, and CD40 (26,(49)(50)(51)(52). The difference in effects on short-term and long-term thymopoiesis and TEC recovery seen between differing input populations of proTs would suggest that using a combination of DN2 and DN3 proTs may be an optimum approach.…”

CCRL1 marks heterogeneity in cortical and medullary thymic epithelial cells

“…The initial formation of Aire + mTECs depended on RANK signals, whereas the continued mTEC development to the involucrin + stage was mapped to the activation of lymphotoxin β receptor (LTβR) signals provided by mature thymocytes [25]. Lkhagvasuren et al reported that CCL21-expressing mTECs contained a cell population distinct from Aire-expressing mTECs and that the accumulation of this CCL21 + Aire -mTEC subpopulation occurred late during postnatal ontogeny [26]. It was also noted that the postnatal accumulation of CCL21 + Aire -mTECs was regulated by LTβR signals [26], of which the ligand lymphotoxin was provided by positively selected thymocytes [25].…”

“…Ribeiro et al [18] further demonstrate that the combination of RANK and CD40 signals, the ligands of which are produced by positively selected thymocytes [8,10], is important for the development of CCRL1-EGFP low mTECs. Thus, the analysis of CCRL1-EGFP reporter mice suggests a novel heterogeneity in postnatal mTECs.It has been shown that mTECs are heterogeneous in terms of the expression of various molecules, including class II MHC, CD80, Aire, and CCL21 [22][23][24][25][26]. White et al described that Aire expression and terminal differentiation within mTECs are temporally separable events that are controlled by distinct mechanisms.…”

“…It has been shown that mTECs are heterogeneous in terms of the expression of various molecules, including class II MHC, CD80, Aire, and CCL21 [22][23][24][25][26]. White et al described that Aire expression and terminal differentiation within mTECs are temporally separable events that are controlled by distinct mechanisms.…”

“…Lkhagvasuren et al reported that CCL21-expressing mTECs contained a cell population distinct from Aire-expressing mTECs and that the accumulation of this CCL21 + Aire -mTEC subpopulation occurred late during postnatal ontogeny [26]. It was also noted that the postnatal accumulation of CCL21 + Aire -mTECs was regulated by LTβR signals [26], of which the ligand lymphotoxin was provided by positively selected thymocytes [25]. The temporally regulated heterogeneity of mTECs may be linked with the developmental switch of hematopoietic cells (e.g.…”