Journal
FRONTIERS IN IMMUNOLOGY
Volume 10, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2019.01629
Keywords
Shh; gamma delta T-cell; thymus; gd NKT; Smoothened; Hedgehog
Categories
Funding
- MRC [MR/P000843/1]
- Wellcome Trust [WT094255/z/10/z]
- Great Ormond Street Hospital Children's Charity [V1270]
- Pfizer [W121785]
- BBSRC London Interdisciplinary Biosciences Consortium (LiDO)
- GOSHCC
- MRC
- NIHR BRC at GOSH
- BBSRC [1903458, BB/I026324/1] Funding Source: UKRI
- MRC [MR/P000843/1] Funding Source: UKRI
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Here we investigate the function of Hedgehog (Hh) signaling in thymic gamma delta T-cell maturation and subset differentiation. Analysis of Hh mutants showed that Hh signaling promotes gamma delta T-cell development in the thymus and influences gamma delta T-cell effector subset distribution. Hh-mediated transcription in thymic gamma delta cells increased gamma delta T-cell number, and promoted their maturation and increased the gamma delta NKT subset, whereas inhibition of Hh-mediated transcription reduced the thymic gamma delta T-cell population and increased expression of many genes that are normally down-regulated during gamma delta T-cell maturation. These changes were also evident in spleen, where increased Hh signaling increased gamma delta NKT cells, but reduced CD27-CD44+ and V gamma 2+ populations. Systemic in vivo pharmacological Smoothened-inhibition reduced gamma delta T-cell and gamma delta NKT cells in the thymus, and also reduced splenic gamma delta T-cell and gdNKT populations, indicating that Hh signaling also influences homeostasis of peripheral gamma delta T-cell populations. Taken together our data indicate that Sonic Hedgehog is an important determinant of gamma delta T-cell effector subset differentiation.
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