The role of γδ T cells in the airways

Based on their T cell receptor expression two distinct T cell populations have been identified and designated as alphabeta and gammadelta T cells. While the specific role of alphabeta T cells is well understood, the specific function of gammabeta T cells remains elusive. Despite the limited knowledge on what gammadelta T cells exactly recognize as their antigen or antigens, several studies have clearly demonstrated that gammadelta T cells are important regulators of immune responses. Studies on gammadelta T cells in the lung have shown that gammadelta T cells influence B and T cell responses. For instance, gammadelta T cells modulate CD4+alphabeta T cells in tuberculosis, and in allergic inflammation they support IgE production. Furthermore, a recent study on their role as part of the innate immune response has demonstrated that gammadelta T cells regulate airway function independently of alphabeta T cells. This novel finding provides an opportunity to review previous studies on gammadelta T cells in the lung of mice and humans. The examination of these data demonstrates that understanding the role of the various subsets of gammadelta T cells will be critical in elucidating their function as "immunosurveillance cells" of the lung.     

Diversity in recognition and function of human γδ T cells

As interest increases in harnessing the potential power of tissue-resident cells for human health and disease, γδ T cells have been thrust into the limelight due to their prevalence in peripheral tissues, their sentinel-like phenotypes, and their unique antigen recognition capabilities. This review focuses primarily on human γδ T cells, highlighting their distinctive characteristics including antigen recognition, function, and development, with an emphasis on where they differ from their αβ T cell comparators, as well as from γδ T cell populations in the mouse. We review the antigens that have been identified thus far to regulate members of the human Vδ1 population and discuss what players are involved in transducing phosphoantigen-mediated signals to human Vγ9Vδ2 T cells. We also briefly review distinguishing features of these cells in terms of TCR signaling, use of coreceptor and costimulatory molecules and their development. These cells have great potential to be harnessed in a clinical setting, but caution must be taken to understand their unique capabilities and how they differ from the populations to which they are commonly compared.     

A role for epithelial γδ T cells in tissue repair

My colleagues and I have a long-term interest in interactions between intraepithelial γδ T cells and neighboring epithelial cells. We have focused our studies on interactions in the thymus, skin, and intestine, and are investigating the development, specificity, and function of these γδ T cells. Our results have defined unique properties of these cells and support a specialized role for epithelial γδ T cells in immune surveillance, wound repair, inflammation, and protection from malignancy.     

Early production of IL-17A by γδ T cells in the trachea promotes viral clearance during influenza infection in mice

The innate immune response generated against influenza infection is critical for the inhibition of viral dissemination. The trachea contains different types of innate immune cells that protect the respiratory tract from pathogen invasion. Among them, γδ T cells have the ability to rapidly generate large amounts of pro-inflammatory cytokines to preserve mucosal barrier homeostasis during infection. However, little is known about their role during the early phase of influenza infection in the airways. In this study, we found that, early after infection, γδ T cells are recruited and activated in the trachea and outnumber αβ T cells during the course of the influenza infection that follows. We also showed that the majority of the recruited γδ T cells express the Vγ4 TCR chain and infiltrate in a process that involves the chemokine receptor CXCR3. In addition, we demonstrated that γδ T cells promote the recruitment of protective neutrophils and NK cells to the tracheal mucosa. Altogether, our results highlight the importance of the immune responses mediated by γδ T cells.     

Protective role of naturally occurring interleukin-17A-producing γδ T cells in the lung at the early stage of systemic candidiasis in mice

Interleukin-17A (IL-17A)-producing γδ T cells differentiate in the fetal thymus and reside in the peripheral tissues, such as the lungs of naïve adult mice. We show here that naturally occurring γδ T cells play a protective role in the lung at a very early stage after systemic infection with Candida albicans. Selective depletion of neutrophils by in vivo administration of anti-Ly6G monoclonal antibody (MAb) impaired fungal clearance more prominently in the lung than in the kidney 24 h after intravenous infection with C. albicans. Rapid and transient production of IL-23 was detected in the lung at 12 h, preceding IL-17A production and the influx of neutrophils, which reached a peak at 24 h after infection. IL-17A knockout (KO) mice showed reduced infiltration of neutrophils concurrently with impaired fungal clearance in the lung after infection. The major source of IL-17A was the γδ T cell population in the lung, and Cδ KO mice showed little IL-17A production and reduced neutrophil infiltration after infection. Early IL-23 production in a TLR2/MyD88-dependent manner and IL-23-triggered tyrosine kinase 2 (Tyk2) signaling were essential for IL-17A production by γδ T cells. Thus, our study demonstrated a novel role of naturally occurring IL-17A-producing γδ T cells in the first line of host defense against C. albicans infection.     

Function of intestinal γδ T cells

Mucosal tissues including the intestine, lung, reproductive tract, and skin form the major interfaces between the outside and internal milieus. Facing the outside is an epithelial cell layer, the epithelium, built on a vascular connective surface. In addition to performing specialized functions, mucosal tissues are sites where immune, epithelial, and neuronal cell types act in concert to maintain tissue integrity and fightin vading pathogens. This article presents the latest findings from my laboratory describing a novel protective function for the intestinal intraepithelial γδ T cells (γδ intraepithelial lymphocytes).     

The promise of γδ T cells and the γδ T cell receptor for cancer immunotherapy

γδ T cells form an important part of adaptive immune responses against infections and malignant transformation. The molecular targets of human γδ T cell receptors (TCRs) remain largely unknown, but recent studies have confirmed the recognition of phosphorylated prenyl metabolites, lipids in complex with CD1 molecules and markers of cellular stress. All of these molecules are upregulated on various cancer types, highlighting the potential importance of the γδ T cell compartment in cancer immunosurveillance and paving the way for the use of γδ TCRs in cancer therapy. Ligand recognition by the γδ TCR often requires accessory/co-stimulatory stress molecules on both T cells and target cells; this cellular stress context therefore provides a failsafe against harmful self-reactivity. Unlike αβ T cells, γδ T cells recognise their targets irrespective of HLA haplotype and therefore offer exciting possibilities for off-the-shelf, pan-population cancer immunotherapies. Here, we present a review of known ligands of human γδ T cells and discuss the promise of harnessing these cells for cancer treatment.     

Harnessing γδ T cells in anticancer immunotherapy

γδ T lymphocytes are involved in the stress response to injured epithelia and in tissue homeostasis by limiting the dissemination of malignant or infected cells and by regulating the nature of the subsequent adaptive immune response. γδ T cells have potent MHC-unrestricted cytotoxicity, a high potential for cytokine release and broad-spectrum recognition of cancer cells, and as such, are attractive effectors for cancer immunotherapy. Current expectations are going beyond ex vivo manipulation of the Vγ9Vδ2 T subset, and target novel γδ T cell subsets, properties or receptors, to harness these unconventional T lymphocytes against cancer. This Opinion article discusses novel aspects of γδ T cell function during the course of anticancer therapies, as well as new avenues for their clinical implementation.     

Human γδ T cells

A numerically small subset of human T lymphocytes expresses a γδ T cell receptor (TCR). These γδ T cells share certain effector functions with αβ T cells as well as with NK cells and NKT cells. The major peripheral blood γδ T cell subset in healthy adults expresses a Vγ9Vδ2 TCR, which recognizes small phosphorylated metabolites referred to as phosphoantigens. Vδ1 γδ T cells mainly occur in the intestine. They recognize the stress-induced MICA/B and CD1c. Furthermore, γδ T cells express a variety of NK cell and pattern-recognition receptors which are responsible for the “fine-tuning” of effector functions. In recent years, γδ T cells start to emerge as a rewarding target for immunotherapeutic strategies against viral infections and cancer. A better understanding of factors that modulate γδ T cell function will further eluminate the potential of these cells.