What We Know and What We Don't Know About the Function of γδ T Cells

ABSTRACT

γδ T cells, long regarded as unconventional relatives of αβ T cells, have emerged as pivotal players in immunity, with unique biology and therapeutic promise. Recent advances in single‐cell multiomics, refined mouse models, and human cohort studies have deepened insights into their TCR–ligand interactions, developmental pathways, and context‐dependent functions. This mini‐review synthesizes current understanding from structural studies of γδ TCR recognition and developmental regulation—including inborn errors of immunity—to adaptive‐like clonal expansions shaped by infection, aging, and environmental cues. It also highlights their dual roles in cancer, where subsets can exert potent cytotoxicity or promote tumor progression, and discusses strategies to optimize their antitumor potential through checkpoint blockade, metabolic modulation, and engineered receptors. Beyond immunity to malignancy, γδ T cells contribute to tissue homeostasis, repair, and regulation of inflammatory processes in diverse organs, influencing outcomes in neuroinflammation, autoimmunity, and fibrotic diseases. Together, these perspectives form the foundation of a special issue in the European Journal of Immunology (https://onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1521‐4141.T‐cells) dedicated to advancing the understanding of γδ T cell biology and clinical potential.

This mini‐review introduces a special issue on γδ T cells in the European Journal of Immunology. It summarizes how recent advances in single‐cell multiomics, mouse models, and human studies have clarified the developmental pathways, TCR–ligand interactions, and adaptive‐like responses of γδ T cells. A thorough understanding of the complex biology of these cells is necessary to unlock their full potential as targets for immunotherapy.

Abbreviations

BTN

butyrophilin

BTNL

butyrophilin‐like

CAR

chimeric antigen receptor

CDR3

complementarity‐determining region 3 (hyper‐diverse region, e.g., of a TCR)

IDO

indoleamine 2,3‐dioxygenase (tryptophan‐catabolizing enzyme)

PD‐1

programmed cell death protein 1

TIGIT

T‐cell immunoreceptor with immunoglobulin and ITIM domains

TRuC

TCR fusion construct

1. Introduction

γδ T cells have long been considered an unusual companion to αβ T cells, with no apparent nonredundant functions in health and disease. However, the field has disproportionately profited from applying recent advances in single‐cell multiomics to refined mouse models and human cohort studies [1]. Therefore, it is a great timing and a pleasure to preface the special issue on γδ T cells in the European Journal of Immunology (https://onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1521‐4141.T‐cells), which comprises twelve reviews and three original research works that feature many aspects of what we know and don't know about γδ T cell function. These contributions cover the most exciting topics, ranging from the distinctive TCR characteristics of the γδ TCR and γδ T cell development, including inborn errors of immunity, to their specific functions in tissue homeostasis, autoimmunity, and anticancer immunity, as well as exploring new ways to empower γδ T cells for immunotherapy (Figure 1).

FIGURE 1.

Current questions in γδ T cell research: understanding development, tissue function, and clinical application. This figure provides a schematic overview of the current questions in γδ T cell research. It covers cutting‐edge topics, including the unique features of γδ TCRs; the development of γδ T cells, including inborn errors of immunity; their specialized roles in tissue homeostasis, autoimmune diseases, and cancer immunity; and innovative strategies to harness γδ T cells for immunotherapy.

2. Functions and Ligands of γδ T Cell Receptors

The TCRs of γδ T cells, namely γδ TCRs, are composed of gamma and delta chains instead of alpha and beta chains in αβ T cells. Currently, “What is recognized by the γδ TCR?” may still be the most challenging question in the field (reviewed in detail previously in [2, 3]). It is assumed that the majority of γδ TCRs can recognize diverse epitopes of their ligands in a manner reminiscent of how antibodies recognize surface antigens [4, 5]. In addition, certain invariant and thus rather “innate” γδ TCRs use germline‐encoded TCR Vγ regions to interact with specific BTN/BTNL family members in a superantigen‐like fashion. The most prominent example is the recognition of phosphoantigen‐binding BTN3A1 and BT2A1 molecules by T cells with invariant Vγ9Vδ2⁺ TCRs [6, 7, 8], for which the molecular basis is revisited by Herrmann and Karunakaran in this issue [9]. Importantly, γδ TCRs are neither restricted to recognizing peptide/MHC complexes nor are they strictly selected against recognizing self‐molecules [10]. At the 11th International γδ T Cell Conference in Toronto in May 2025, however, Erin Adams suggested that γδ T cells should not generally be described as “not MHC‐restricted” because up to 20% of γδ TCRs may react with MHC or MHC‐related molecules in some way. It was agreed that future trials will have to determine whether this estimation is in the right ballpark. Indeed, of few interactions between γδ TCRs and cognate ligands that have been verified biochemically or structurally, most show a bias for binding MHC‐like surface proteins such as T22 and CD1d [11, 12]. However, recognition of MHC Class I or Class II molecules by γδ TCRs can be dependent [13] or independent [14] of presented peptides, and interactions are often not involving the CDR3 regions of the γδ TCR [15].

To investigate how certain γδ TCRs instruct the phenotype of maturing tissue‐specific and functional subsets of γδ T cells in thymus and periphery, Winkler and colleagues have recently generated the first in situ transgenic TCR knock‐in mouse with a fixed monoclonal TCR delta chain [16]. Here, they review their surprising observation that a single Vδ1 chain can support the development of basically all known mouse γδ T cell subsets and further discuss novel implications regarding the environmental cues and the transcriptional regulation that drive γδ T cells toward a CD8αα⁺ intraepithelial lymphocyte phenotype [17]. As the γδ TCR defines the γδ T cell lineage, it is obviously required for γδ T cell development [18]. However, the development and function of αβ and γδ T cells seem to be differentially affected by inborn errors of immunity. In their review, Sagar and Ehl elucidate the impact of inborn genetic errors as well as induced variations on the development of human γδ T cells [19]. Along this line, earlier work from the Malissen lab showed that proper γδ TCR signaling is required for a “quality control” positive selection of γδ T cells [20, 21]. In contrast, it is less clear how important the γδ TCR is for γδ T cell function in the periphery [22]. Some intraepithelial γδ T cells are constantly receiving signals through their γδ TCR [23, 24]. Yet, information about γδ T cells losing these signals via genetic ablation is sparse [25, 26].

Advocating for an instructive role of the γδ TCR for the differentiation of mature γδ T cells in the periphery, high‐throughput γδ TCR analyses revealed that most humans acquire highly expanded persisting γδ clones at some point in their life [27, 28]. These findings are consistent with an adaptive‐like immune response in all γδ T cells that do not use invariant Vγ9Vδ2⁺ TCRs, which are associated with a more innate immune response. This has stimulated research into the conditions under which γδ T cells expand. Focusing on human γδ T cell population dynamics from birth to old age, Ravens and Tolosa discuss that recent multiomic approaches have advanced our understanding of γδ T‐cell development in the thymus and their functional adaptation to the microbial environment in the periphery [29]. In addition, original research from the Vermijlen group is contributing new, exciting data to the general understanding of the life cycle of human γδ T cells. This research reports how the human γδ TCR repertoire is shaped by sepsis in an age‐ and pathogen‐dependent manner [30], and how maternal administration of probiotics augments IL‐17‐committed γδ T cells in newborns [31].

3. γδ T Cells Against Cancer

The intrinsic ability of γδ T cells to recognize and attack malignancies independently of tumor antigen presentation by MHC molecules exposes their translational potential for cancer treatment in situations where neoantigen‐specific αβ T cells are inefficient. This has stimulated growing translational interest in γδ T cells, bringing them out of the shadows of αβ T cells and into the spotlight [32]. Although promising results have emerged from clinical trials investigating the use of γδ T cells in anticancer therapy, some problems remain unresolved and further research is necessary [33].

In particular, current research investigating how antitumor reactivity of γδ T cells is achieved focuses on the role of the γδ TCR. Seminal studies reported that individual Vδ1⁺ γδ TCRs seem to be specifically reactive and potentially protective against hitherto unknown ligands expressed by limited sets of cancer types [34]. However, blocking the checkpoints PD‐1 and TIGIT may be required to unlock the full antitumor cytotoxicity of Vδ1⁺ γδ T cells infiltrating melanoma, Merkel cell carcinoma, or colorectal cancer [35, 36]. Indeed, adoptive γδ T cell therapy seems to work best in combination with immune checkpoint blockade and modulation of cytotoxic receptors [37, 38].

The translation of γδ T cells to therapies against tumors is further complicated by observations that some γδ T cell subsets may even promote tumor growth. Fiala and colleagues address these issues by discussing the pro‐ and antitumorigenic functions of γδ T cells [39]. They summarize the mechanisms by which γδ T cells exert seemingly contradictory effector functions due to their preferential production of the antitumor IFN‐γ or pro‐tumor IL‐17A, and cast light on the functions of human γδ T cells in cancer. Furthermore, it is important to explore and eventually modify the mechanisms by which γδ T cells infiltrate solid tumors and how the tumor microenvironment influences γδ T cell function, e.g., through IDO overexpression and galectin crosstalk. Here, Wistuba‐Hamprecht and colleagues review the spatial dimension for the proper function and organization of tumor‐invasive human γδ T cells [40]. γδ T cells may be specifically manipulated and engineered to perform better in antitumor assays and ultimately in antitumor therapies. Concepts to enhance the antitumor effector functions and ensure optimized clinical efficacy include culturing γδ T cells in the presence of vitamin C, as explained by Kabelitz and colleagues [41]. Other concepts propose to equip in vitro expanded γδ T cells with classical chimeric antigen receptors (CARs), or to use tumor‐reactive γδ TCRs as “natural CARs.” Accordingly, extending the horizon of how γδ T cells still represents an unearthed treasure for immunotherapy. To this end, Schamel and colleagues review the potential of CAR γδ T cells and TRuC γδ T cells. They also provide a detailed discussion of the current implications, safety, and obstacles of using engineered γδ T cells in cancer therapy [42].

4. Tissue‐Specific Functions of γδ T Cells

In addition to their anticancer reactivity, established functions of γδ T cells include warranting tissue homeostasis, surveillance, and regeneration. They also have non‐immunological functions, such as thermogenesis and modulation of cognitive processes via γδ T cells residing in the central nervous system [43]. In this special issue, Bulgur and colleagues review γδ T cell functions in the central nervous system, highlighting upcoming challenges in the field and providing new insights into potential therapeutic strategies. The authors speculate about the molecular mechanisms behind their findings on the contribution of γδ T cells to neuropathophysiology. They recently pioneered the identification of an embryonically derived Vγ6⁺ γδ T cell subset that infiltrates the meninges from birth and comprises most IL‐17‐producing cells [44]. The authors further suggest that γδ T cells may be responsible for triggering or preventing inflammatory responses in neurodegenerative diseases as well as neuropsychiatric disorders [45].

Next are reviews on the roles of γδ T cells in autoinflammatory spondylarthritides [46], immune‐mediated kidney diseases (including glomerulonephritis) [47], recovery of the ischemic brain after stroke [48], and a study on the role of γδ T cells in the pathobiology of experimental lung fibrogenesis [49]. These reviews complement the section on the functions of γδ T cells in tissue homeostasis and regeneration. γδ T cells have also been implicated in chronic inflammatory skin diseases such as psoriasis. In this disease, IL‐17‐producing dermal γδ T cells switch toward aerobic glycolysis, contributing to disease severity and relapse [50]. In models of inflammatory bowel disease, IL‐17A‐producing γδ T cells promote intestinal inflammation in an IL‐23‐dependent manner. However, under steady‐state conditions, these cells can also exhibit protective functions in epithelial repair [51]. These contributions highlight the central role of γδ T cells in Type 3 immunity and inflammatory diseases along the IL‐23/IL‐17 cytokine axis. While γδ T cells are a major, if not the primary, source of IL‐17A and IL‐17F in mouse tissues, IL‐17 cytokine production by γδ T cells appears to be more tightly regulated in humans and restricted to specific subsets such as Vγ9Vδ2 T cells under inflammatory conditions [52].

In conclusion, this special issue offers substantial, novel insights into mouse and human γδ T cell development and the role of γδ T cells in various inflammatory diseases. At the same time, it highlights their potential for immunotherapy against cancer.

Conflicts of Interest

The authors declare no conflicts of interest.

Peer Review

The peer review history for this article is available at https://publons.com/publon/10.1002/eji.70058.

Prinz I. and Meyer A., “What We Know and What We Don't Know About the Function of γδ T Cells.” European Journal of Immunology 55, no. 9 (2025): e70058. 10.1002/eji.70058

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.