Sonic Hedgehog Is a Determinant of γδ T-Cell Differentiation in the Thymus

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.