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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.

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Skint-1 Expression Occurs Independently of Aire, and Aire−/− Mice Display Normal Development of Invariant Vγ5+ DETCs(A) Quantitative PCR analysis of expression of the indicated genes in neonatal thymuses from WT (white bars) and Aire−/− (black bars) mice.(B and C) Epidermal preparations from WT and Aire−/− neonates were analyzed by flow cyometry for the presence of CD3+ T cells (B), together with antibodies to the Vγ5TCR (C).(D) Frequency of CD3+Vγ5+ DETCs in WT (white bars) and Aire−/− (black bars) neonates. n.s. is not significant.
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fig7: Skint-1 Expression Occurs Independently of Aire, and Aire−/− Mice Display Normal Development of Invariant Vγ5+ DETCs(A) Quantitative PCR analysis of expression of the indicated genes in neonatal thymuses from WT (white bars) and Aire−/− (black bars) mice.(B and C) Epidermal preparations from WT and Aire−/− neonates were analyzed by flow cyometry for the presence of CD3+ T cells (B), together with antibodies to the Vγ5TCR (C).(D) Frequency of CD3+Vγ5+ DETCs in WT (white bars) and Aire−/− (black bars) neonates. n.s. is not significant.

Mentions: To investigate whether the importance of Rank-dependent Aire+ mTEC development for Skint-1-mediated DETC maturation is directly dependent upon Aire itself, we analyzed Skint1 expression and the emergence of epidermal Vγ5+ DETCs in neonatal Aire-deficient mice. We found that in contrast to the known Aire dependency of genes such as Spt1 (salivary protein 1) (Figure 7A), Skint1 expression was unaltered in Aire−/− neonatal thymus (Figure 7A). In line with this lack of requirement for Aire in the expression of Skint1, comparison of the neonatal epidermis of Aire−/− and WT mice showed no changes in the frequency of epidermal CD3+ cells (Figure 7B), including those expressing Vγ5+ (Figures 7C and 7D). Thus, despite the association between the maturation of Aire+ mTECs and invariant Vγ5TCR+ DETC maturation, Aire deficiency does not impair the emergence of an invariant Skint-1-dependent DETC pool.


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)

Skint-1 Expression Occurs Independently of Aire, and Aire−/− Mice Display Normal Development of Invariant Vγ5+ DETCs(A) Quantitative PCR analysis of expression of the indicated genes in neonatal thymuses from WT (white bars) and Aire−/− (black bars) mice.(B and C) Epidermal preparations from WT and Aire−/− neonates were analyzed by flow cyometry for the presence of CD3+ T cells (B), together with antibodies to the Vγ5TCR (C).(D) Frequency of CD3+Vγ5+ DETCs in WT (white bars) and Aire−/− (black bars) neonates. n.s. is not significant.
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Related In: Results  -  Collection

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

fig7: Skint-1 Expression Occurs Independently of Aire, and Aire−/− Mice Display Normal Development of Invariant Vγ5+ DETCs(A) Quantitative PCR analysis of expression of the indicated genes in neonatal thymuses from WT (white bars) and Aire−/− (black bars) mice.(B and C) Epidermal preparations from WT and Aire−/− neonates were analyzed by flow cyometry for the presence of CD3+ T cells (B), together with antibodies to the Vγ5TCR (C).(D) Frequency of CD3+Vγ5+ DETCs in WT (white bars) and Aire−/− (black bars) neonates. n.s. is not significant.
Mentions: To investigate whether the importance of Rank-dependent Aire+ mTEC development for Skint-1-mediated DETC maturation is directly dependent upon Aire itself, we analyzed Skint1 expression and the emergence of epidermal Vγ5+ DETCs in neonatal Aire-deficient mice. We found that in contrast to the known Aire dependency of genes such as Spt1 (salivary protein 1) (Figure 7A), Skint1 expression was unaltered in Aire−/− neonatal thymus (Figure 7A). In line with this lack of requirement for Aire in the expression of Skint1, comparison of the neonatal epidermis of Aire−/− and WT mice showed no changes in the frequency of epidermal CD3+ cells (Figure 7B), including those expressing Vγ5+ (Figures 7C and 7D). Thus, despite the association between the maturation of Aire+ mTECs and invariant Vγ5TCR+ DETC maturation, Aire deficiency does not impair the emergence of an invariant Skint-1-dependent DETC pool.

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