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Redefining thymus medulla specialization for central tolerance
#MMPMID28830910
Cosway EJ
; Lucas B
; James KD
; Parnell SM
; Carvalho-Gaspar M
; White AJ
; Tumanov AV
; Jenkinson WE
; Anderson G
J Exp Med
2017[Nov]; 214
(11
): 3183-3195
PMID28830910
show ga
During ??T cell development, the thymus medulla represents an essential
microenvironment for T cell tolerance. This functional specialization is
attributed to its typical organized topology consisting of a branching structure
that contains medullary thymic epithelial cell (mTEC) networks to support
negative selection and Foxp3(+) T-regulatory cell (T-reg) development. Here, by
performing TEC-specific deletion of the thymus medulla regulator lymphotoxin ?
receptor (LT?R), we show that thymic tolerance mechanisms operate independently
of LT?R-mediated mTEC development and organization. Consistent with this, mTECs
continue to express Fezf2 and Aire, regulators of intrathymic self-antigens, and
support T-reg development despite loss of LT?R-mediated medulla organogenesis.
Moreover, we demonstrate that LT?R controls thymic tolerance by regulating the
frequency and makeup of intrathymic dendritic cells (DCs) required for effective
thymocyte negative selection. In all, our study demonstrates that thymus medulla
specialization for thymic tolerance segregates from medulla organogenesis and
instead involves LT?R-mediated regulation of the thymic DC pool.
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