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2018 ; 13
(2
): e0193188
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Thymic epithelial cell-derived signals control B progenitor formation and
proliferation in the thymus by regulating Let-7 and Arid3a
#MMPMID29462197
Xiao S
; Zhang W
; Manley NR
PLoS One
2018[]; 13
(2
): e0193188
PMID29462197
show ga
The postnatal thymus is an efficient microenvironment for T cell specification
and differentiation. B cells are also present in the thymus and have been
recently shown to impact T cell selection, however, the mechanisms controlling B
cell development in the thymus are largely unknown. In Foxn1lacZ mutant mice,
down-regulation of Foxn1 expression in thymic epithelial cells beginning 1 week
after birth caused a dramatic reduction of T progenitors and an increase of B
cell progenitors. This time point is coincident with the switch from fetal to
adult-type hematopoietic stem cells (HSCs), which is regulated by the Lin28-Let7
system. We hypothesize that the thymic environment might regulate this process to
suppress fetal-type B cell development in the thymus. In this study we show that
in the Foxn1lacZ thymus, although the down-regulation of Lin28 in thymocytes was
normal, up-regulation of Let-7 was impaired. The failure to up-regulate Let-7
caused a transient increase of Arid3a in B precursors, which is known to promote
fetal-type B cell fate. Over-expression of Lin28a in HSCs also reduced Let-7 and
promoted Arid3a expression in BM and thymic B progenitors, increasing B cell
production in the thymus. The level of Let-7 in thymic B progenitors was up
regulated by in vitro co-culture with IL15, Vitamin-D3, and retinoic acid, thus
down-regulating Arid3a to promote B cell differentiation. All of these signals
were produced in thymic epithelial cells (TECs) related to Let-7 expression in
thymic B progenitors, and down-regulated in Foxn1lacZ mutants. Our data show that
signals provided by TEC control thymic B cell development by up-regulating Let-7,
suppressing Arid3a expression in intrathymic progenitor B cells to limit their
proliferation during the neonatal to adult transition.