Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

Abstract

γδ T-cells perform a wide range of tissue and disease specific functions that are dependent on the effector cytokines produced by these cells. However, the aggregate signals required for the development of interferon-γ (IFNγ) and interleukin-17 (IL-17) producing γδ T-cells remain unknown. Here, we define the cues involved in the functional programming of γδ T-cells, by examining the roles of T-cell receptor (TCR), Notch, and cytokine-receptor signaling. KN6 γδTCR-transduced Rag2−/− T-cell progenitors were cultured on stromal cells variably expressing TCR and Notch ligands, supplemented with different cytokines. We found that distinct combinations of these signals are required to program IFNγ versus IL-17 producing γδ T cell subsets, with Notch and weak TCR ligands optimally enabling development of γδ17 cells in the presence of IL-1β, IL-21 and IL-23. Notably, these cytokines were also shown to be required for the intrathymic development of γδ17 cells. Together, this work provides a framework of how signals downstream of TCR, Notch and cytokine receptors integrate to program the effector function of IFNγ and IL-17 producing γδ T-cell subsets.

IL ‐7‐dependent compositional changes within the γδ T cell pool in lymph nodes during ageing lead to an unbalanced anti‐tumour response

“…While peripheral cd1 T cells are mainly replenished by thymic output, cd17 T cells are thought to be derived exclusively from foetal thymus and maintained by proliferation and self-renewal in the periphery [58,67]. Only under certain circumstances-involving TCR stimulation in the presence of IL-1b and IL-23-can cd17 T cells develop in adult mice [35,51,52]. We did not find increased levels of IL-1b or IL-23 in the pLN of old mice but discovered that IL-7 is highly expressed in the aged pLNs and the number of cd T cells correlates with the amount of IL-7.…”

Immunology & Cell Biology's top 10 original research articles 2017–2018

“…Zarin et al . Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation …”

“…The cellular signals that regulate lymphocyte activation, differentiation and survival are also well represented in the top ICB articles and include the contribution of G protein‐coupled receptors (GPR65 and GPR174) in suppressing T‐cell activation and autoimmune activity, the integration of Notch and cytokine signals in generating γδ T‐cell subsets, and the role of the immunoproteosome subunit LMP2 in promoting lymphocyte survival . Wirasinha et al .…”

“…Using fetal thymus organ culture, Zarin et al . explore the signaling requirements for the generation of IFN‐γ‐ and IL‐17‐producing γδ T‐cell subsets and how these signals integrate into a differentiation program . Finally, to investigate the signals promoting the survival of lymphocytes, Zanker et al .…”

“…The cellular signals that regulate lymphocyte activation, differentiation and survival are also well represented in the top ICB articles and include the contribution of G proteincoupled receptors (GPR65 and GPR174) in suppressing Tcell activation and autoimmune activity, 2,5 the integration of Notch and cytokine signals in generating cd T-cell subsets, 10 and the role of the immunoproteosome subunit LMP2 in promoting lymphocyte survival. 9 Wirasinha et al make the novel discovery that a deficiency in GPR65 results in more severe disease using an experimental model of multiple sclerosis, but despite having a defect in survival, CD4 T cells from GPR65-deficient mice were not responsible for the exacerbated disease.…”