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Murine γδ 17 cells, which are T cells that bear the γδ T cell receptor (TCRγδ) and secrete interleukin-17A (IL-17A), are generated in the thymus and are critical for various immune responses. Although strong TCRγδ signals are required for the development of interferon-γ (IFN-γ)-secreting γδ cells (γδ IFN cells), the generation of γδ 17 cells requires weaker TCRγδ signaling. Here, we demonstrated that constrained activation of the kinase Syk downstream of TCRγδ was required for the thymic development of γδ 17 cells. Increasing or decreasing Syk activity by stimulating TCRγδ or inhibiting Syk, respectively, substantially reduced γδ 17 cell numbers. This delimited Syk activity optimally engaged the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway, which maintained the expression of master regulators of the IL-17 program, RORγt and c-Maf. Inhibition of PI3K not only abrogated γδ 17 cell development but also augmented the development of a distinct, previously undescribed subset of γδ T cells. These CD8 + Ly6a + γδ T cells had a type-I IFN gene expression signature and expanded in response to stimulation with IFN-β. Collectively, these studies elucidate how weaker TCRγδ signaling engages distinct signaling pathways to specify the γδ 17 cell fate and identifies a role for type-I IFNs in γδ T cell development., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Whether thymocytes adopt an αβ or a γδ T cell fate in the thymus is determined at the β selection checkpoint by the relatively weak or strong signals that are delivered by either the pre-T cell receptor (preTCR) or the γδ TCR, respectively. Signal initiation at the β selection checkpoint is thought to be independent of ligand engagement of these receptors. Some reports have suggested that receptor oligomerization, which is thought to be mediated by either the immunoglobulin (Ig)-like domain of the preTCRα (pTα) chain or the variable domain of TCRδ, is a unifying mechanism that initiates signaling in early CD4(-)CD8(-) double-negative (DN) thymocyte progenitors. Here, we demonstrate that the extracellular regions of pTα and TCRδ that are implicated in mediating receptor oligomerization were not required for signal initiation from the preTCR or TCRγδ. Indeed, a truncated TCRγδ that lacked all of its extracellular Ig-like domains still formed a signaling-competent TCR that drove cells through the β selection checkpoint. These observations suggest that signal initiation in DN thymocytes is simply a consequence of the surface-pairing of TCR chains, with signal strength being a function of the abundances of surface TCRs. Thus, processes that regulate the surface abundances of TCR complexes in DN cells, such as oligomerization-induced endocytosis, would be predicted to have a major influence in determining whether cells adopt an αβ versus γδ T cell fate.

The thymus gives rise to two T cell lineages, alphabeta and gammadelta, that are thought to develop independently of one another. Hence, double positive (DP) thymocytes expressing CD4 and CD8 coreceptors are usually viewed simply as progenitors of CD4+ and CD8+ alphabeta T cells. Instead we report that DP cells regulate the differentiation of early thymocyte progenitors and gammadelta cells, by a mechanism dependent on the transcription factor RORgt, and the lymphotoxin (LT) beta receptor (LTbetaR). This finding provokes a revised view of the thymus, in which lymphoid tissue induction-type processes coordinate the developmental and functional integration of the two T cell lineages.