IL-7-dependent compositional changes within the γδ T cell pool in lymph nodes during ageing lead to an unbalanced anti-tumour response.
O'Brien, Louise McNeill
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Chen, H., Eling, N., Martinez-Jimenez, C. P., O'Brien, L. M., Carbonaro, V., Marioni, J., Odom, D., & et al. (2019). IL-7-dependent compositional changes within the γδ T cell pool in lymph nodes during ageing lead to an unbalanced anti-tumour response.. EMBO reports, 20 (8), e47379. https://doi.org/10.15252/embr.201847379
ABSTRACT How the age-associated decline of immune function leads to increased cancer incidence is poorly understood. Here, we have characterised the cellular composition of the gd T cell pool in peripheral lymph nodes (pLNs) upon ageing. We find that ageing has minimal cell-intrinsic effects on function and global gene expression of gd T cells, and gdTCR diversity remains stable. However, ageing alters TCRd chain usage and clonal structure of gd T cell subsets. Importantly, IL-17-producing gd17 T cells dominate the gd T cell pool of aged mice - mainly due to the selective expansion of Vg6+ gd17 T cells and augmented gd17-polarisation of Vg4+ T cells. Expansion of the gd17 T cell compartment is mediated by increased IL-7 expression in the T cell zone of old mice. In a Lewis lung cancer model, pro-tumourigenic Vg6+ gd17 T cells are exclusively activated in the tumour-draining LN and their infiltration into the tumour correlates with increased tumour size in aged mice. Thus, upon ageing, substantial compositional changes of the gd T cell pool in the pLN lead to an unbalanced gd T cell response in the tumour that is associated with accelerated tumour growth.
Lymph Nodes, T-Lymphocyte Subsets, Animals, Mice, Inbred C57BL, Mice, Carcinoma, Lewis Lung, Receptors, Antigen, T-Cell, gamma-delta, Interleukin-7, Interleukin-17, Tumor Burden, Immunophenotyping, Signal Transduction, Cell Differentiation, Gene Expression Regulation, Neoplastic, Cell Lineage, Aging
This work has been funded by Cancer Research UK (H-CC, CPMJ, VC, DTO, JCM, and MdlR), Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (WT107609 awarded to MdlR) (LMOB), EMBL international PhD programme (NE), Janet Thornton Fellowship (WT098051 awarded to CPMJ), European Research Council (615 584, DTO), EMBO Young Investigators Programme (DTO), EMBL (JCM), and the Wellcome Sanger Institute (CPMJ, JCM, and DTO).
WELLCOME TRUST (107609/Z/15/Z)
Cancer Research UK (C14303_do not transfer)
European Research Council (615584)
Cancer Research UK (20412)
Wellcome Trust (202878/Z/16/Z)
External DOI: https://doi.org/10.15252/embr.201847379
This record's URL: https://www.repository.cam.ac.uk/handle/1810/293285