Intrathymic programming of effector fates in three molecularly distinct γδ T cell subtypes (115.16)

Abstract Two distinct lineages of T cells, distinguished by expression of either an αβ or γδ T cell receptor (TCR), arise from a common progenitor in the thymus. The type of pathogen and the cytokine milieu directs effector differentiation of αβ T cells in the periphery through the induction of specific transcriptional networks. γδ T cell development is distinct from that of αβ T cells in its ordered rearrangement of TCR genes and the pairing of Vγ and Vδ chains to generate γδ T cell subsets that home to specific tissues. While γδ T cells have primarily been studied as one homogenous population, they can be functionally classified into effector subsets based on the production of signature cytokines, analogous to αβ T helper subsets. Unlike αβ T cells, γδ T cell effector function correlates with genomically encoded TCR chains, but the mechanism of γδ effector specification is unclear. In conjunction with the Immunological Genome Project Consortium, we performed a high resolution transcriptome analysis of all emergent γδ thymocyte subsets segregated based on TCRγ/δ chain usage and maturation state in the thymus. Our data indicate the existence of three separate subtypes of γδ T cells in the thymus. The profiles of the emergent immature γδ T cell subsets are already embedded with unique gene programs directing subset-specific effector function, indicating that γδ T cell effector function is molecularly programmed in the thymus prior to, or concurrent with, TCR expression.