Rank Signaling Links the Development of Invariant γδ T Cell Progenitors and Aire+ Medullary Epithelium

• Published in: Immunity (Cambridge, Mass.) Vol. 36; no. 3; pp. 427 - 437
• Main Authors: Roberts, Natalie A., White, Andrea J., Jenkinson, William E., Turchinovich, Gleb, Nakamura, Kyoko, Withers, David R., McConnell, Fiona M., Desanti, Guillaume E., Benezech, Cecile, Parnell, Sonia M., Cunningham, Adam F., Paolino, Magdalena, Penninger, Josef M., Simon, Anna Katharina, Nitta, Takeshi, Ohigashi, Izumi, Takahama, Yousuke, Caamano, Jorge H., Hayday, Adrian C., Lane, Peter J.L., Jenkinson, Eric J., Anderson, Graham
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.03.2012; Cell Press
• Subjects: AIRE Protein; Animals; Cell Differentiation - immunology; Cellular Microenvironment; Epithelial Cells - immunology; Female; Fetus - cytology; Fetus - immunology; Male; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Knockout; Precursor Cells, T-Lymphoid - cytology; Precursor Cells, T-Lymphoid - immunology; Pregnancy; Receptor Activator of Nuclear Factor-kappa B - immunology; Receptors, Antigen, T-Cell, gamma-delta - metabolism; Signal Transduction - immunology; Thymus Gland - cytology; Thymus Gland - immunology; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - immunology
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2012.01.016

The thymic medulla provides a specialized microenvironment for the negative selection of T cells, with the presence of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) during the embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance. Here we showed that emergence of the first cohorts of Aire+ mTECs at this key developmental stage, prior to αβ T cell repertoire selection, was jointly directed by Rankl+ lymphoid tissue inducer cells and invariant Vγ5+ dendritic epidermal T cell (DETC) progenitors that are the first thymocytes to express the products of gene rearrangement. In turn, generation of Aire+ mTECs then fostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the emergence of an invariant DETC repertoire. Hence, our data attributed a functional importance to the temporal development of Vγ5+ γδ T cells during thymus medulla formation for αβ T cell tolerance induction and demonstrated a Rank-mediated reciprocal link between DETC and Aire+ mTEC maturation. [Display omitted] ► Invariant Vγ5+ thymocytes regulate formation of Aire+ medullary thymic epithelium ► Generation of an invariant Vγ5+ T cell population requires thymus medulla development ► Skint-1-mediated Vγ5+ thymocyte development is Aire independent ► Dependency on Tnfrsf11a links γδ T cell and medullary epithelium development