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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Martinez-Jimenez, Celia Pilar  ORCID logo  https://orcid.org/0000-0002-9534-6201
O'Brien, Louise McNeill 
Carbonaro, Valentina  ORCID logo  https://orcid.org/0000-0003-0915-6901

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 γδ 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 γδ T cells, and γδTCR diversity remains stable. However, ageing alters TCRδ chain usage and clonal structure of γδ T-cell subsets. Importantly, IL-17-producing γδ17 T cells dominate the γδ T-cell pool of aged mice-mainly due to the selective expansion of Vγ6+ γδ17 T cells and augmented γδ17 polarisation of Vγ4+ T cells. Expansion of the γδ17 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 Vγ6+ γδ17 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 in γδ T-cell pool in the pLN lead to an unbalanced γδ T-cell response in the tumour that is associated with accelerated tumour growth.

Description

Keywords

IL-7, ageing, lymph node, tumour response, γδ T-cell lineage, Aging, Animals, Carcinoma, Lewis Lung, Cell Differentiation, Cell Lineage, Gene Expression Regulation, Neoplastic, Immunophenotyping, Interleukin-17, Interleukin-7, Lymph Nodes, Mice, Mice, Inbred C57BL, Receptors, Antigen, T-Cell, gamma-delta, Signal Transduction, T-Lymphocyte Subsets, Tumor Burden

Journal Title

EMBO Rep

Conference Name

Journal ISSN

1469-221X
1469-3178

Volume Title

20

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (107609/Z/15/Z)
Cancer Research UK (C14303/A17197)
European Research Council (615584)
Cancer Research UK (20412)
Wellcome Trust (202878/Z/16/Z)
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).