Gamma delta (γδ) T cells are a small subset of CD3-positive T cells in the peripheral blood but occur at increased frequency in mucosal tissues in mice and humans (1). Murine and human γδ T cells make up a minor part (1–5%) of the circulating T cell compartment found in the blood and secondary lymphoid organs. However, certain subsets of γδ T cells are present in much higher proportions (10–100%) in epithelial tissues, such as the reproductive tract, skin epidermis, and gastrointestinal tract (2). The mouse γδ T cell subsets are distinguished by different T cell receptor(TCR) Vγ chains, whereas human γδ T cell subsets are often distinguished by Vγ chain usage (2).

Heilig and Tonegawa’s nomenclature proposed in 1986 segregated mouse γδ T cells into six distinct subsets: Vγ1, Vγ2, Vγ4, Vγ5, Vγ6, and Vγ7 (3). Meanwhile, the human γ chain locus consists of four subgroups; VγI includes Vγ2, 3, 4, 5, and 8. Among the three other Vγ subgroups, only Vγ9 (from the VγII group) is functional when using the nomenclature of Lefranc and Rabbitts (4). Besides, γδ T cells are reported to bridge the gap between innate and adaptive immune responses in mice and humans. Although γδ bearing cells were shown to constitute a minor proportion of peripheral T lymphocytes, their co-evolution with αβ T cells and B lymphocytes revealed non-redundant functions.

γδ T cells mostly reside within tissues, particularly in epithelial layers, where they might play tissue-protective or inflammatory roles (5). Experiments in mice have demonstrated that γδ T cells are predominantly tissue-resident immune cells (6, 7). From further mouse studies, it is nonetheless becoming increasingly clearer that the γδ T pool residing in a given tissue is the result of the wave of development from fetal to adult life, referred to as layered ontogeny (8). Nevertheless, how the ontogeny of γδ T cells differs between tissues remains obscure. Although the origin of tissue-resident γδ T cells in humans is technically challenging to address, there is evidence that the local γδ T cells pool can partially be replenished by infiltration and in situ differentiation of circulating naïve γδ T cells (9).

Reflecting their tissue residency and the impact of the microenvironment on γδ T cell function, recent studies have revealed profound tissue-specific transcriptional signatures for human (9) and mouse γδ T cells (10). Accumulating evidence suggests that γδ T cells are shaped by the microenvironment and exert tissue-specific functions depending on the signals they receive. This review summarizes recent studies on the tissue-specific features of γδ T cells across organs in mice and humans. We discuss the phenotypic differences that contribute to distinct γδ T cell profiles in different tissues, highlighting the similarities and differences between mice and humans. Understanding how various tissue microenvironments impact γδT cells is important for improving therapeutic strategies in pathologies that affect specific tissues.

αβ T cells and γδ T cells arise from a common progenitor known as a double-negative cell (DN; lacking CD4 and CD8 expression) in the thymus (11). γδ T cells that develop without pre-programming in the thymus and receive the TCR signal in the periphery develop as adaptive types, whereas γδ T subsets that receive the signal in the thymus are innate types, and those which receive the TCR signal in the periphery but during an early phase of life get converted into innate-like γδ T cells (12).

During the development of mouse γδ T cells, γδ T cells are the first T cells to develop in the mouse embryonic thymus and appear as early as embryonic day 15 of gestation. These cells express a monoclonal Vγ5Vδ1 T cell receptor (TCR) and are always located in the skin epidermis. A few days later, by an oligoclonal Vγ6Vδ1 TCR-expressing population, entered multiple peripheral locations, including the tongue, dermis, uterus, testis, abdominal cavity, adipose tissue, and meninges. Semi-invariant Vγ4⁺ γδ T cells also develop within this time range, and these cells are associated with Vγ6⁺ cells that have the same functional characteristics. Such Vγ4⁺ γδ T cells are home to the lungs, the dermis of the skin, and lymph nodes. Subsequent perinatal Vγ7⁺ γδ T cell waves enter the intestine, followed by polyclonal Vγ1⁺ and Vγ4⁺ γδ T cell populations, which are more systematically distributed, including peripheral lymphoid organs, where they exhibit adaptive behavior when activated (revised Figure 1A ).

On the other hand, mouse γδ T cells can commit to effector cytokine production during thymic development; two main functional subsets have been extensively described: IFN-γ-producing γδ T cells and IL-17-producing γδ T cells. (i) IFN-γ-producing γδ T cells express surface markers, such as CD45RB and CD27. Subpopulations include the fetal and perinatally derived Vγ5⁺ dendritic epidermal T cells (which is called DETC), which are home to the skin, and the postnatally generated cells that express more polyclonal γδ T cell receptor (TCRs) (mostly Vγ1⁺ or Vγ4⁺) and localize to lymphoid tissues. (ii) IL-17-producing γδ T cells lack CD27 expression and include the fetal derived monoclonal and/or oligoclonal Vγ6⁺ T cells that are home to the tongue, dermis, uterus, testis, adipose tissue, and brain meninges, and the Vγ4⁺ IL-17-producing γδ T cells that express multiple semi-invariant TCRs and are home to the lung, dermis, and lymph nodes.

The development of mouse γδ T cells and their subsets depends critically on IL-7 and IL-15 (5). The growth of dermal γδ T cells preferentially requires IL-7, whereas IL-15 is mandatory for the generation of γδ TCR-expressing intra-epithelial lymphocytes (IELs) (13). IL-7 signaling promotes the development of IL-17-producing γδ T cells, whereas IL-15 and IL-2 induce IFN-γ secretion. Besides, various cytokines have been reported to affect the differentiation of effector γδ T cells. IL-12 and IL-18 promote IFN-γ production, while IL-1β and IL-23 drive them towards IL-17-producing cells (14).

In summary, these very curious ‘waves’ of mouse γδ T cell development ensure that most peripheral tissues are effectively colonized by long-lived γδ T cells (Revised Figure 1A ) that are ideally placed to play important roles in situ.

Unlike murine γδ T cells, human γδ T cells are usually sub-divided based on the use of one of two variable regions of TCR-δ chains, which is Vδ1 or Vδ2. The Vγ9 and Vδ2 variable (V) gene segments are the first γ/δ chains to undergo rearrangement in development, detected in the fetal liver from as early as at weeks 5~6 of gestation (15) and in the fetal thymus after 8 weeks of gestation (16). By mid-gestation (20~30 weeks), Vγ9Vδ2⁺ T cells dominate the γδ repertoire (Revised Figure 1B ). Vδ2 is the largest subset of circulating human γδ T cells in the blood, which gets rapidly recruited to the mucosal surface to participate in the clearance of localized infection (17). Functionally, Vδ2⁺ T cells exist as naive (CD45RA⁺CD27⁺), central memory (CD45RA⁻ CD27⁺), effector memory (CD45RA⁻ CD27⁻), and terminally differentiated (CD45RA⁺CD27⁻) populations (18). By contrast, human Vδ1⁺ subsets are the major γδ T cells population in the intestine and skin, whereas Vδ3⁺ subsets are enriched in the liver and gut.

Several features of the Vγ9Vδ2⁺ compartment suggest similarities to mouse γδ T-cell subsets (19). First, the early fetal wave of Vγ9Vδ2⁺ production, with the semi-invariant Vγ9Vδ2⁺ TCR repertoire, mirrors early waves of semi-invariant mouse γδ T cells. Second, the semi-invariant mouse population expresses Vγ4 sequences of restricted length and diversity, analogous to public human Vγ9 sequences (20, 21). Third, consistent with related immunobiology, butyrophilins (BTN3A1 and BTN3A2/3) are important for Vγ9Vδ2⁺ T cell recognition (22). However, while some semi-invariant mouse γδ T cell populations can become hyporesponsive to TCR triggering following initial strong TCR signaling during development (23), apparently, this does not apply to human Vγ9Vδ2⁺ T cells. Notably, Vγ9Vδ2⁺ T cells remain responsive to both pyrophosphate antigens (pAg) and anti-CD3 stimulation, a feature that underlies their potential use in several cancer immunotherapy applications (24), and they also exhibit the potential for further TCR-mediated plasticity (25).

In summary, γδ T cells comprise distinct functional subpopulations. Current views in the field suggest that the functional potential of mouse γδ T cells is related to the use of Vγ, while the functional potential of humans is related to the use of Vδ (26). When assembling TCRs, human γδ T cells express seven bona fide Vγ genes but only three Vδ genes (27).

Recent reports have undoubtedly revealed significant tissue-specific functions of γδ T cells. We highlight the distribution, features, and specific markers of distinct subsets of murine and human γδ T cells (Revised Table 1 ). In humans, γδ T cells in blood display a quiescent state and migratory behavior reminiscent of naiüve T cells. By contrast, γδ T cells in peripheral organs make up a spectrum of activation states that differ depending on the organ. Although human γδ T cells deserve more research, mouse γδ T cells display tissue-specific degrees of IFN-γ and IL-17A production that appear to be regulated by factors present in the tissues, such as cytokines. γδ T cells subsets in different organs show variable means of sensing the microenvironment, particularly regarding cytokines. Finally, the tissue-specific functions of γδ T cells, in terms of tissue retention and response to chemokines/cytokines, are not only related to the organ but also to species. Further elucidation of γδ T cell-mediated tissue immunity, particularly in humans, will be necessary to improve the development of tissue-specific immunomodulatory drugs to be used, for example, in inflammatory conditions and cancer.

GQ and SW helped in drafting the manuscript. ZZ and DJ helped draw the image in Figures 1 , 2 . JL and AL conceptualized and revised the manuscript. All authors contributed to the article and approved the submitted version.

This work was supported by a grant from the National Natural Science Foundation of China (31900657 to JL).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.