Limits...
Rank signaling links the development of invariant γδ T cell progenitors and Aire(+) medullary epithelium.

Roberts NA, White AJ, Jenkinson WE, Turchinovich G, Nakamura K, Withers DR, McConnell FM, Desanti GE, Benezech C, Parnell SM, Cunningham AF, Paolino M, Penninger JM, Simon AK, Nitta T, Ohigashi I, Takahama Y, Caamano JH, Hayday AC, Lane PJ, Jenkinson EJ, Anderson G - Immunity (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Immune Regulation, University of Birmingham, Birmingham, B15 2TT, UK.

Show MeSH

Related in: MedlinePlus

Skint1 Expression Maps to CD80+ mTECs and Is Regulated by Rank Signaling(A) Quantitative PCR analysis of Aire and Skint1 in freshly isolated TEC subsets.(B) 2-dGuo-treated FTOC cultured in the presence (black bars) or absence (white bars) of Rank antibody were analyzed by qPCR for expression of Aire and Skint1. Levels of expression in total CD45− FTOC stroma (hatched bars) are shown for comparison.(C) qPCR analysis of the indicated genes in CD45− cells isolated from WT (white bars) and Tnfrsf11a−/− (black bars) E15 thymus lobes, established in FTOC for 7 days. In all cases, levels of mRNA were normalized to β-actin.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3368267&req=5

fig3: Skint1 Expression Maps to CD80+ mTECs and Is Regulated by Rank Signaling(A) Quantitative PCR analysis of Aire and Skint1 in freshly isolated TEC subsets.(B) 2-dGuo-treated FTOC cultured in the presence (black bars) or absence (white bars) of Rank antibody were analyzed by qPCR for expression of Aire and Skint1. Levels of expression in total CD45− FTOC stroma (hatched bars) are shown for comparison.(C) qPCR analysis of the indicated genes in CD45− cells isolated from WT (white bars) and Tnfrsf11a−/− (black bars) E15 thymus lobes, established in FTOC for 7 days. In all cases, levels of mRNA were normalized to β-actin.

Mentions: Intrathymic development of invariant Vγ5+ thymocyte progenitors and the generation of an invariant Vγ5+ DETC population in the epidermis depends upon thymic stromal cell expression of Skint-1, an Ig superfamily member expressed by mTECs (Lewis et al., 2006). To investigate the possible link between this thymic stromal cell expression of Skint-1, the medullary accumulation of Vγ5+ thymocytes, and Aire+ mTEC development, we further analyzed Skint1 expression in embryonic cTEC and mTEC subsets (Shakib et al., 2009), including immature CD80− and mature CD80+ mTEC populations shown previously to have a direct precursor-product relationship, with the latter containing Aire+ cells (Gäbler et al., 2007; Gray et al., 2007; Rossi et al., 2007). As expected, Aire expression was limited to mature CD80+ mTECs (Figure 3A), but of note this restricted pattern mirrored that of Skint1, which was undetectable in immature and mature stages of the cTEC lineage and in immature CD80− mTECs (Figure 3A).


Rank signaling links the development of invariant γδ T cell progenitors and Aire(+) medullary epithelium.

Roberts NA, White AJ, Jenkinson WE, Turchinovich G, Nakamura K, Withers DR, McConnell FM, Desanti GE, Benezech C, Parnell SM, Cunningham AF, Paolino M, Penninger JM, Simon AK, Nitta T, Ohigashi I, Takahama Y, Caamano JH, Hayday AC, Lane PJ, Jenkinson EJ, Anderson G - Immunity (2012)

Skint1 Expression Maps to CD80+ mTECs and Is Regulated by Rank Signaling(A) Quantitative PCR analysis of Aire and Skint1 in freshly isolated TEC subsets.(B) 2-dGuo-treated FTOC cultured in the presence (black bars) or absence (white bars) of Rank antibody were analyzed by qPCR for expression of Aire and Skint1. Levels of expression in total CD45− FTOC stroma (hatched bars) are shown for comparison.(C) qPCR analysis of the indicated genes in CD45− cells isolated from WT (white bars) and Tnfrsf11a−/− (black bars) E15 thymus lobes, established in FTOC for 7 days. In all cases, levels of mRNA were normalized to β-actin.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368267&req=5

fig3: Skint1 Expression Maps to CD80+ mTECs and Is Regulated by Rank Signaling(A) Quantitative PCR analysis of Aire and Skint1 in freshly isolated TEC subsets.(B) 2-dGuo-treated FTOC cultured in the presence (black bars) or absence (white bars) of Rank antibody were analyzed by qPCR for expression of Aire and Skint1. Levels of expression in total CD45− FTOC stroma (hatched bars) are shown for comparison.(C) qPCR analysis of the indicated genes in CD45− cells isolated from WT (white bars) and Tnfrsf11a−/− (black bars) E15 thymus lobes, established in FTOC for 7 days. In all cases, levels of mRNA were normalized to β-actin.
Mentions: Intrathymic development of invariant Vγ5+ thymocyte progenitors and the generation of an invariant Vγ5+ DETC population in the epidermis depends upon thymic stromal cell expression of Skint-1, an Ig superfamily member expressed by mTECs (Lewis et al., 2006). To investigate the possible link between this thymic stromal cell expression of Skint-1, the medullary accumulation of Vγ5+ thymocytes, and Aire+ mTEC development, we further analyzed Skint1 expression in embryonic cTEC and mTEC subsets (Shakib et al., 2009), including immature CD80− and mature CD80+ mTEC populations shown previously to have a direct precursor-product relationship, with the latter containing Aire+ cells (Gäbler et al., 2007; Gray et al., 2007; Rossi et al., 2007). As expected, Aire expression was limited to mature CD80+ mTECs (Figure 3A), but of note this restricted pattern mirrored that of Skint1, which was undetectable in immature and mature stages of the cTEC lineage and in immature CD80− mTECs (Figure 3A).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Immune Regulation, University of Birmingham, Birmingham, B15 2TT, UK.

Show MeSH
Related in: MedlinePlus