TY - JOUR
T1 - Redefining thymus medulla specialization for central tolerance
AU - Cosway, Emilie J.
AU - Lucas, Beth
AU - James, Kieran D.
AU - Parnell, Sonia M.
AU - Carvalho-Gaspar, Manuela
AU - White, Andrea J.
AU - Tumanov, Alexei V.
AU - Jenkinson, William E.
AU - Anderson, Graham
N1 - Publisher Copyright:
© 2017 Cosway et al.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - During αβT 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 β receptor (LTβR), we show that thymic tolerance mechanisms operate independently of LTβR-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 LTβR-mediated medulla organogenesis. Moreover, we demonstrate that LTβR 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 LTβR-mediated regulation of the thymic DC pool.
AB - During αβT 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 β receptor (LTβR), we show that thymic tolerance mechanisms operate independently of LTβR-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 LTβR-mediated medulla organogenesis. Moreover, we demonstrate that LTβR 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 LTβR-mediated regulation of the thymic DC pool.
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U2 - 10.1084/jem.20171000
DO - 10.1084/jem.20171000
M3 - Article
C2 - 28830910
AN - SCOPUS:85033401118
SN - 0022-1007
VL - 214
SP - 3183
EP - 3195
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 11
ER -