Dangerous γδ T cells in aged mice

Abstract

Progressive susceptibility to tumors and infectious diseases in the elderly are a serious threat to public health in aging societies. For this reason, there is growing interest in mechanisms and predictive biomarkers that accompany and potentially cause this process. In this issue of EMBO Reports, Chen et al [1] report the surprising finding that a specific subset of γδ T cells with very limited clonal diversity strongly expands in lymph nodes of aging mice. These T cells uniformly express a T‐cell receptor (TCR) composed of a Vγ6 and a Vδ1 chain and show an effector T‐cell phenotype characterized by the swift production of the pro‐inflammatory cytokine interleukin‐17 (IL‐17) upon ex vivo stimulation (γδT17 cells). Since γδT17 cells are suspected to be pro‐tumorigenic [2], the authors next compared how mice of different age coped with an experimental lung cancer challenge and found impaired anti‐tumor responses in old mice. Based on these observations, they propose a link between changes of the composition of γδ T cells in the aging lymph nodes and increased risk of cancer development in aged mice.

Previous monitoring studies across the lifespan of humans reported perturbations of immune cell composition in the elderly, for example, a gradual loss of B cells and αβ T cells and an increase in the number of cells with markers of NK cell activity 3. Further, inversion of the 2:1 ratio of CD4⁺/CD8⁺ T cells in peripheral blood is a striking marker for immune senescence associated with increased morbidity and mortality. However, since most such studies were conducted using peripheral blood samples, mechanistic clues of these markers are still limited. Here, Chen et al compared the composition and numbers of γδ T cells in peripheral lymph nodes (pLN) of old (> 21 months) and young adult mice (3 months old). They made the seminal observation that the frequency of γδ T cells among all T cells of a given pLN was increased twofold in old mice. Strikingly, more than 50% of those increased γδ T cells were strongly biased toward a γδT17‐committed phenotype as assessed by surface markers 4 and intracellular cytokine staining after ex vivo stimulation. TCR repertoire sequencing analyses further confirmed that these γδT17 cells predominantly expressed a canonical Vγ6⁺Vδ1⁺ γδ TCR and to a lesser extent a set of Vγ4⁺ γδ TCR with limited clonal diversity. Importantly, those observations were very reproducible analyzing mice derived from different unrelated animal facilities and thus likely establish a generalized phenomenon independent of any local microbiota.

Whether increasing proportions of γδT17 cells might also confer a potential benefit to aging mice remains speculation. However, higher levels of γδT17 cells are mainly regarded as pro‐tumor due to their support for tumor engraftment and vascularization 2. Using an experimental model for lung cancer, the authors next investigated the correlation between changes in the composition of γδ T cells in aging lymph nodes and an increased risk of cancer development. Indeed, they could show that pro‐tumorigenic γδT17 cells were exclusively activated in the tumor‐draining pLN and their infiltration into the tumor correlated with increased tumor size in aged mice (Fig 1). Of note, the drug FTY720 that induces T‐cell retention in pLN could inhibit the migration of γδ T cells into the tumor.

Figure 1. Altered composition of the γδ T‐cell pool in lymph nodes during aging enhances tumor growth.

The pool of γδ T cells in peripheral lymph nodes (pLN) is dominated by IFN‐γ‐producing γδT1 cells in young mice (left). These γδT1 cells can be recruited to exert anti‐tumor functions within lung tumors. Upon aging, IL‐7 levels within pLN increase over time and support maintenance and gradual expansion of Vγ6⁺ and Vγ4⁺ IL‐17‐producing γδ T cells. This shifts the balance of γδT1 cells versus IL‐17‐producing γδT17 cells toward predominating γδT17 cells in old mice and results in an altered pro‐tumorigenic T‐cell composition within lung tumors in old mice. Migration from pLN to tumor tissue of both γδT1 cells and γδT17 cells can be inhibited by administration of the immunomodulating drug FTY720.

The findings of Chen et al raise a number of additional mechanistic questions. How do the γδT17 cells get into pLN, and why do they have a selective advantage to survive there? First, while other γδ T cells are mainly replenished by thymic output throughout adulthood, γδT17 cells, and in particular the Vγ6⁺Vδ1⁺ γδ T cells that accumulate in aging pLN, are thought to be derived exclusively from fetal thymus and maintained by proliferation and self‐renewal in the periphery 5. It follows that these γδT17 cells must have an enormous longevity and expansion capacity. Whether their accumulation in aging pLN is a consequence of either higher proliferation rates or increased survival as compared to other lymphocytes competing for the same niche remains yet unclear. However, interleukin‐7 is an important factor for γδT17 cell homeostasis 6. Therefore, the authors went the extra mile to show that homeostasis of Vγ6⁺ T cells in pLN was strictly dependent on interleukin‐7 secreted by stromal fibroblastic reticular cells and lymphatic endothelial cells.

Second, it is currently emerging that dermal γδT17 cells are constantly leaving their tissue of residence in response to local signals and migrate to skin‐draining pLN 7. The nature of these signals, which lead to a down‐regulation of CD69 and increased S1PR1 expression, remains elusive 7. Therefore, and although this current study 1 did not observe any impact of housing conditions in diverse animal facilities, it appears likely that skin microbiota and exposure to pathogens are critically involved. Germ‐free mice showed a specific decrease of Vγ6⁺ T‐cell numbers in mucosal tissues but also in skin‐draining lymph nodes 8. Furthermore, an invasive intestinal infection with Listeria monocytogenes led to the accumulation of large numbers of Vγ6⁺ T cells in the intestine‐draining mesenteric lymph nodes 9, which otherwise show rather low numbers and proportions of γδT17 cells. Together, these observations may hint toward an unexpected mechanistic link between microbial exposure, accumulation of γδT17 cells and draining lymph nodes, and tumor development. Interestingly, such connections could even bypass the lymph nodes in organs that contain large numbers of tissue‐resident γδT17 cells 10.

Overall, Chen et al report an increase of very potent effector T cells in pLN with age. At present, we can only speculate about the (beneficial) physiologic functions of such γδT17 cell accumulation and how this information is relevant for the human system. They may provide an innate responsiveness to infectious agents arriving at the pLN via the lymph, and at the same time might constitute a reservoir of cells that support inflammatory responses in peripheral tissues.

EMBO Reports (2019) 20: e48678