Biology subjects

Gascoigne, N. R. J.

Publications and source records attributed to Gascoigne, N. R. J..

3 recordsLinked to original sources

bioRxiv2026

Uni-TINT: Unifying T and Innate Lymphoid Cell Taxonomy with a high resolution, pan-disease and pan-tissue single-cell transcriptomic atlas

T cells and innate lymphoid cells (ILCs) exhibit extensive phenotypic diversity across tissues and diseases, yet inconsistent annotation limits cross-study comparisons and biological interpretation. We present Uni-TINT, an integrated pan-disease and pan-tissue atlas comprising 3.46 million cells from 1,869 samples spanning 194 studies, 166 disease subtypes, and 66 tissue types. Through systematic, hierarchical manual annotation, Uni-TINT establishes a unified and context-aware taxonomy of T and ILC populations, resolving 207 cell subtypes and states across conventional and unconventional T cells, natural killer (NK) cells, helper ILCs, thymocytes, and hematopoietic progenitors. We identified an immunosuppressive, tumour-associated CD4 T regulatory population which we validated with spatial transcriptomics. Other rare and unconventional populations characterised included CD8 regulatory T cells, invariant NKT cells and memory-like NK cells. Integration of T cell receptor sequencing suggested functional associations between {gamma}{delta} T cell co-receptor expression and TRDV gene usage. Finally, a comparative analysis of healthy and diseased immature cells identified a small population of malignant hematopoietic stem cells carrying chromosomal aberrations and enriched in acute leukaemia of mixed phenotype. Together, Uni-TINT provides a unified reference framework for immune annotation and discovery across health and disease.

immunology↗

bioRxiv2025

Themis dominates T cell exhaustion by regulation of TCR and PD-1 signaling

T cell exhaustion is important to protect the host from immunopathology during chronic viral infection, but it also impairs T cell anti-tumor immunity1-5. A fundamental unresolved question is whether and how T cell exhaustion is determined at the onset of TCR signaling6-8. Here we report an unexpected role of Themis, a TCR-proximal signaling molecule9, in T cell exhaustion. Chronic viral infection in mice usually leads to T cell exhaustion and survival of the host. Surprisingly, Themis T-cell conditional knockout mice died from severe CD8+-dependent lung immunopathology in chronic viral infection, showing Themis importance in establishing T cell exhaustion. We found that Themis-deficient CD8+ T cells were hyperactivated at the single-cell level - producing more TNF and IFN{gamma} compared to wild-type counterparts - but defective in population-level expansion. Moreover, TCF-1 and TOX expression were inhibited in Themis-deficient CD8+ T cells, thereby impairing differentiation of exhausted T cell precursors (T-pex) and maintenance of terminally exhausted T cells (T-ex), respectively. Mechanistically, Themis initially promotes TCR signaling to induce PD-1 expression and subsequently mediates PD-1 signaling. In the latter, Themis binds to PD-1 and promotes PD-1 phosphorylation and its recruitment of SHP2, thereby acting as a negative regulator to inhibit T cell effector functions. Without Themis, the orderly regulation of TCR and PD-1 signaling, and therefore exhaustion, is disrupted. Thus, our results unequivocally demonstrate that Themis-mediated early TCR signaling plays a decisive role in T cell exhaustion and provide a novel mechanism of PD-1 signaling through Themis.

immunology↗

bioRxiv2022

IL-12/18/21 pre-activation enhances the anti-tumor efficacy of expanded γδT cells and overcomes resistance to anti-PD-L1 treatment

{gamma}{delta}T cells are promising candidates for cellular immunotherapy due to their immune regulation through cytokine production and MHC-independent direct cytotoxicity against a broad spectrum of tumors. However, current {gamma}{delta}T cell-based cancer immunotherapy has limited efficacies and novel strategies are needed to improve its clinical outcomes. Here, we report that cytokine pre-treatment with IL-12/18, IL-12/15/18, IL-12/18/21 and IL-12/15/18/21 could effectively enhance the activation and cytotoxicity of in vitro expanded murine and human {gamma}{delta}T cells. However, only adoptive transfer of IL-12/18/21 pre-activated {gamma}{delta}T cells significantly inhibited tumor growth in a murine melanoma model and a hepatocellular carcinoma model. Both IL-12/18/21 pre-activated antibody-expanded and zoledronate-expanded human {gamma}{delta}T cells effectively controlled tumor growth in a humanized mouse model. IL-12/18/21 pre-activation promoted {gamma}{delta}T cell proliferation and cytokine production in vivo and enhanced IFN-{gamma} and TNF- production, as well as granzyme B expression by endogenous CD8+ T cells in a cell-cell contact dependent manner. Furthermore, the adoptive transfer of IL-12/18/21 pre-activated {gamma}{delta}T cells could overcome the resistance to anti-PD-L1 therapy, and the combination therapy had a synergistic effect on the therapeutic outcomes. Moreover, the enhanced anti-tumor function of adoptively transferred IL-12/18/21 pre-activated {gamma}{delta}T cells was largely diminished in the absent of endogenous CD8+T cells when administered alone or in combination with anti-PD-L1, suggesting a CD8+T cell-dependent mechanism. Taken together, IL-12/18/21 pre-activation could promote {gamma}{delta}T cell anti-tumor function and overcome the resistance to checkpoint blockade therapy, indicating an effective combinational cancer immunotherapeutic strategy. SynopsisO_LIIL-12/18/21 pre-activation enhances the anti-tumor efficacy of adoptively transferred {gamma}{delta}T cells by promoting its proliferation, activation, and cytotoxicity, as well as activating endogenous CD8+ T cells. C_LIO_LIAdoptive transfer of IL-12/18/21 pre-activated {gamma}{delta}T cells could overcome the resistance to anti-PD-L1 therapy, indicating an effective combinational cancer immunotherapeutic strategy. C_LI

immunology↗