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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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Defective Intrathymic Maturation of Vγ5+ DETC Progenitors in Relb-Deficient Mice(A) Analysis of Vγ5TCR+ thymocyte maturation in WT and Relb-deficient E15 thymus lobes placed in FTOCs for 5 days. Numbers indicate the percentages of cell populations.(B) Percentages of immature Vγ5+CD45RBlo and mature Vγ5+CD45RBhi thymocytes in WT (black bars) and Relb-deficient (white bars) FTOCs. A minimum of six mice were analyzed, and an unpaired Student's two-tailed t test was performed with asterisks signifying a significant difference, where p < 0.0001.
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fig4: Defective Intrathymic Maturation of Vγ5+ DETC Progenitors in Relb-Deficient Mice(A) Analysis of Vγ5TCR+ thymocyte maturation in WT and Relb-deficient E15 thymus lobes placed in FTOCs for 5 days. Numbers indicate the percentages of cell populations.(B) Percentages of immature Vγ5+CD45RBlo and mature Vγ5+CD45RBhi thymocytes in WT (black bars) and Relb-deficient (white bars) FTOCs. A minimum of six mice were analyzed, and an unpaired Student's two-tailed t test was performed with asterisks signifying a significant difference, where p < 0.0001.

Mentions: To study the potential link between Aire+ mTECs and Vγ5+ DETC progenitors, we initially studied the embryonic thymus of Relb−/− mice, a transcription factor in the alternative NF-κB signaling pathway that is downstream of several TNFSF-R family members including CD40 and Rank, known regulators of mTEC maturation. Consistent with this, and as previously reported, Aire+ mTECs were absent from the thymus of E17 Relb−/− embryos (data not shown). When we analyzed Vγ5+ thymocyte development, with upregulation of CD45RB as a marker of maturation (Lewis et al., 2006), we found a statistically significant decrease in both CD45RBlo and CD45RBhi subsets in Relb−/− embryonic thymuses compared to WT controls (Figures 4A and 4B). Despite a reduction in both CD45RB subsets, a dramatic skewing in the ratio (approximately 6:1) of WT:Relb−/− CD45RBhi cells was observed, compared to a ratio of 1.6:1 for WT:Relb CD45RBlo cells, suggesting that although RelB may play a subtle role in the initial emergence of Vγ5CD45RBlo cells, it appears critically important in the maturation to the Vγ5+CD45RBhi stage.


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)

Defective Intrathymic Maturation of Vγ5+ DETC Progenitors in Relb-Deficient Mice(A) Analysis of Vγ5TCR+ thymocyte maturation in WT and Relb-deficient E15 thymus lobes placed in FTOCs for 5 days. Numbers indicate the percentages of cell populations.(B) Percentages of immature Vγ5+CD45RBlo and mature Vγ5+CD45RBhi thymocytes in WT (black bars) and Relb-deficient (white bars) FTOCs. A minimum of six mice were analyzed, and an unpaired Student's two-tailed t test was performed with asterisks signifying a significant difference, where p < 0.0001.
© Copyright Policy
Related In: Results  -  Collection

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

fig4: Defective Intrathymic Maturation of Vγ5+ DETC Progenitors in Relb-Deficient Mice(A) Analysis of Vγ5TCR+ thymocyte maturation in WT and Relb-deficient E15 thymus lobes placed in FTOCs for 5 days. Numbers indicate the percentages of cell populations.(B) Percentages of immature Vγ5+CD45RBlo and mature Vγ5+CD45RBhi thymocytes in WT (black bars) and Relb-deficient (white bars) FTOCs. A minimum of six mice were analyzed, and an unpaired Student's two-tailed t test was performed with asterisks signifying a significant difference, where p < 0.0001.
Mentions: To study the potential link between Aire+ mTECs and Vγ5+ DETC progenitors, we initially studied the embryonic thymus of Relb−/− mice, a transcription factor in the alternative NF-κB signaling pathway that is downstream of several TNFSF-R family members including CD40 and Rank, known regulators of mTEC maturation. Consistent with this, and as previously reported, Aire+ mTECs were absent from the thymus of E17 Relb−/− embryos (data not shown). When we analyzed Vγ5+ thymocyte development, with upregulation of CD45RB as a marker of maturation (Lewis et al., 2006), we found a statistically significant decrease in both CD45RBlo and CD45RBhi subsets in Relb−/− embryonic thymuses compared to WT controls (Figures 4A and 4B). Despite a reduction in both CD45RB subsets, a dramatic skewing in the ratio (approximately 6:1) of WT:Relb−/− CD45RBhi cells was observed, compared to a ratio of 1.6:1 for WT:Relb CD45RBlo cells, suggesting that although RelB may play a subtle role in the initial emergence of Vγ5CD45RBlo cells, it appears critically important in the maturation to the Vγ5+CD45RBhi stage.

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