Evolved to protect, designed to destroy: IL‐17‐producing γδ T cells in infection, inflammation, and cancer

Abstract

T cells of the gamma delta (γδ) lineage are evolutionary conserved from jawless to cartilaginous and bony fish to mammals and represent the "swiss army knife" of the immune system capable of antigen-dependent or independent responses, memory, antigen presentation, regulation of other lymphocytes, tissue homeostasis, and mucosal barrier maintenance, to list a few. Over the last 10 years, γδ T cells that produce the cytokine IL-17 (γδT17) have taken a leading position in our understanding of how our immune system battles infection, inflicts tissue damage during inflammation, and gets rewired by the tumor microenvironment. A lot of what we know about γδT17 cells stems from mouse models, however, increasing evidence implicates these cells in numerous human diseases. Herein, we aim to give an overview of the most common mouse models that have been used to study the role of γδT17 cells in infection, inflammation, and cancer, while at the same time we will evaluate evidence for their importance in humans. We hope and believe that in the next 10 years, means to take advantage of the protective and destructive properties of γδ T and in particular γδT17 cells will be part of our standard immunotherapy toolkit.

The Diverse Roles of γδ T Cells in Cancer: From Rapid Immunity to Aggressive Lymphoma

“…The faceted roles of γδ T cells in cancer are shaped by multiple regulators that determine whether they take on a pro- or anti-tumour role, very much depending on their initial effector type programming [ 33 , 34 , 35 ], the tumour microenvironmental context [ 36 , 37 , 38 ], encounters with other tumour-associated immune cells [ 39 , 40 ] and the tumour entities themselves [ 41 , 42 ]. Indeed, γδ T cells are critical cells in cancer as well as in general immunity [ 2 , 43 ]; they are the first T cells to develop [ 44 ], leave the embryonic thymus and home to their target tissues [ 45 ]. Here, they are found throughout the entirety of life as deeply embedded into the cellular organisational structure [ 46 , 47 ].…”

“…Generally, murine γδ T cells can be functionally subtyped into RAR-related orphan receptor gamma (RORγt)-programmed interleukin-17A (IL-17)-producing γδ T (γδT17) cells [ 10 , 43 ] and T-box 21 (T-bet)-programmed interferon-γ (IFN-γ)-producing γδ T (γδT1) cells [ 48 ]. There is a clear association between TCR Vγ chain usage and effector subtype: murine Vγ1 + , Vγ5 + and Vγ7 + γδ T cells are biased towards IFN-γ production, whereas Vγ4 + and Vγ6 + γδ T cells largely produce IL-17 ( Figure 1 ).…”

“…In humans, it has been until recently very difficult to study this subtype due to their rarity, tissue-resident nature and lack of protocols for their in vitro expansion. However, recent advancements in this area have facilitated the study of γδT17 cells and their pro-tumour functions in humans [ 43 ]. Herein, we focus mainly on the roles of human γδ T-cell subsets in cancer immunity, where possible.…”

“…The promotion of angiogenesis is another key tumour-promoting effect of γδT17 cells in solid cancers [ 43 ] ( Figure 3 ). In mice, it was first demonstrated that tumour-infiltrating γδ T cells, polarised towards a γδT17 phenotype by the TME, provided the main source of tumour IL-17 necessary to induce increased levels of angiogenic factors Ang-2 and VEGF, as well as increase blood vessel numbers [ 162 ].…”

The Mysterious Actor—γδ T Lymphocytes in Chronic Lymphocytic Leukaemia (CLL)

“…γδ T cells are involved in autoimmune diseases [ 42 ], asthma [ 43 ] and infection surveillance [ 44 , 45 ]. Both Vδ1 and Vδ2 subsets express high cytotoxic potential and are important in cancer immunosurveillance [ 35 , 46 ].…”