γδT cells in IBD: beneficial or detrimental?

γδT cells in IBD: beneficial or detrimental? | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Immunology This is a preprint and has not been peer reviewed. Data may be preliminary. 11 March 2025 V1 Latest version Share on γδT cells in IBD: beneficial or detrimental? Authors : Baoqing Xu , Jianbin Ji , Lingling Ma , Chunyan Wang , Lianjing Pang , QingChao Song , Yang Liu , Zhenghua Zhou , and Fanfan Qu [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174171866.69230736/v1 Published Immunology Version of record Peer review timeline 319 views 268 downloads Contents Abstract 1. Introduction 2. γδT cells Overview 3. γδT cells and immunity 4 γδT cells and IBD 5. Conclusions and prospects Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Immune cells are crucial in the body’s defence mechanisms. γδT cells are a non-traditional subpopulation of T cells with distinct structures and functions. γδT cells exhibit unique immune functions, contribute to both innate and adaptive immunity, and are implicated in several immune disorders. An increasing number of studies have identified changes in γδT cell numbers, types, and secreted cytokines in IBD. However, whether γδT cells in IBD are beneficial or detrimental remains controversial. Several studies have explored γδT cell-based therapies for immune disorders, and γδT cell-based therapy for IBD has emerged as a promising research direction. There are numerous reviews of γδT cells and autoimmune diseases, but few reviews focus on γδT and IBD. Therefore, this article briefly summarizes the current understanding of γδT cells in IBD. γδT cells in IBD: beneficial or detrimental? Baoqing Xu 1,2 , Jianbin Ji 1 , Lingling Ma 1 , Chunyan Wang 1 , Lianjing Pang 1 , QingChao Song 1 , Yang Liu 1,2 , Zhenghua Zhou 1* , Fanfan Qu 1* 1 First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China. 2 Tianjin University of Traditional Chinese Medicine, Tianjin, China. Co-corresponding authors: Fanfan Qu and Zhenghua Zhou * Correspondence: Corresponding Author. First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, No. 88, Changling Road, Xiqing District, Tianjin, 300381, China. Co-corresponding authors: Fanfan Qu ( [email protected] ) and Zhenghua Zhou ( [email protected] ) Telephone number: (022)27986653 Funding This work was supported by the National Natural Science Foundation of China (82374351); the Tianjin Health Science and Technology Project (TJWJ2024QN033); the Tianjin Municipal Education Commission Scientific Research Program (2023KJ151) Conflicts of Interest The authors declare no potential conflicts of interest. Abstract Immune cells are crucial in the body’s defence mechanisms. γδT cells are a non-traditional subpopulation of T cells with distinct structures and functions. γδT cells exhibit unique immune functions, contribute to both innate and adaptive immunity, and are implicated in several immune disorders. An increasing number of studies have identified changes in γδT cell numbers, types, and secreted cytokines in IBD. However, whether γδT cells in IBD are beneficial or detrimental remains controversial. Several studies have explored γδT cell-based therapies for immune disorders, and γδT cell-based therapy for IBD has emerged as a promising research direction. There are numerous reviews of γδT cells and autoimmune diseases, but few reviews focus on γδT and IBD. Therefore, this article briefly summarizes the current understanding of γδT cells in IBD. Keywords γδT cell; Inflammatory bowel disease; Autoimmune disease 1. Introduction Immune cells are essential to the body’s defence mechanisms. B cells are responsible for humoral immunity and antibody synthesis, while T cells are crucial for cellular immunity. Additionally, natural killer cells (NK cells) can induce apoptosis in infected or malignant cells. Among these immune cells, γδT cells represent a non-conventional subset of T cells, classified into various subpopulations according to their structure and function. They are enriched in epithelial tissues such as human skin, lungs, and intestines. With remarkable plasticity and unique functional properties, γδT cells contribute to diverse physiological processes including immune regulation, inflammatory responses, and tumor surveillance. γδT cells serve as a link between innate and adaptive immunity and are implicated in various autoimmune diseases. γδT cells have gained significant attention in immunotherapy research in recent years. Inflammatory bowel disease (IBD) is a chronic, episodic inflammatory condition of the intestine, primarily encompassing ulcerative colitis (UC) and Crohn’s disease (CD) [1] . The primary clinical manifestations include abdominal pain, diarrhea, weight loss, and intestinal bleeding [2] . Etiology involves complex interactions between genetic, environmental and microbiological factors and the immune response [3] . In IBD, impaired innate immunity and dysregulation of the gut microbiota activate the adaptive immune system, resulting in an inflammatory response that causes tissue damage [4] . Although γδT cells play a unique role in IBD, their exact functions remain contentious. Some research indicates a beneficial effect while other studies propose a detrimental impact. An increasing number of preclinical and clinical research focused on the relationship between γδT cells and IBD, aiming to elucidate the mechanisms and develop γδT cell-based therapeutic strategies. There are many reviews on γδT and autoimmune diseases. There are still fewer reviews on γδT and IBD, therefore, this paper systematically reviews γδT cells in IBD. 2. γδT cells Overview γδT cells are a distinct subpopulation of lymphocytes characterized by innate and adaptive immunity [5] . They were first identified in 1987 [6] . γδT cells develop from progenitor T cells in the thymus and expand and mature outside the thymus [7] . These cells have high plasticity and can be categorized into various subpopulations, each exhibiting distinct immune functions and secreting multiple cytokines under diverse environmental conditions. Although γδT cells constitute only a small fraction of the human circulation, around 1-5% of the total T cells in peripheral blood, they are significantly concentrated in the epithelial layer of barrier organs, including the respiratory tract, the skin and intestinal mucosa [8] . This paper briefly summarizes the structure, differentiation and function of γδT cells, as shown in Figure 1. 2.1 γδT cell structure The T cell receptor (TCR) comprises four peptide chains: α, β, γ, and δ. Based on the surface expression of the TCR, T cells are categorized into two primary groups: αβT cells and γδT cells. Both originate from CD4 - CD8 - double negative thymocytes in the thymus, where γδT cells mature before αβTs [9] . Based on cell surface characteristics, αβT cells, the predominant lymphocyte type in the peripheral circulation, are separated into two primary subpopulations: CD4 + and CD8 + T cells [10] . The TCR on γδT cells consists of a heterodimer formed by γ and δ chains. It expresses seven distinct Vγ TCR chains (Vγ2, 3, 4, 5, 8, 9, 11), which can be combined with any of the four Vδ chains (Vδ1, 2, 3, 5) [11] . Humans possess only six expressed Vγ genes: Vγ2, Vγ3, Vγ4, Vγ5, Vγ8, and Vγ9 [12] . γδT cells are not restricted by major histocompatibility complex (MHC), and their antigen recognition does not rely on the processing and subsequent presentation of MHC molecules by antigen-presenting cells (APCs). Most γδT cells do not express CD4 and CD8 molecules [13] , but a few can express CD4 or CD8 and are able to participate in immunoregulation and immune response. Human γδT cells can be categorized into distinct subpopulations according to their TCR expression [14] , and there is no obvious functional deviation of γδT cells with different TCR chains [5] .Based on the expression of the δ chain of γδT cells, the major human cell subpopulations can be classified into Vδ1T cells, Vδ2T cells and Vδ3T cells. Vδ1T cells are primarily located in the intestinal epithelium, skin, liver and spleen, with a limited presence in circulating blood. Vδ1 is able to express many Vγ chains, including Vγ2-Vγ10, resulting in the formation of different cellular subpopulations [15] . These cells exhibit significant cytotoxicity and possess the advantage of being tissue-resident [16] . They can produce cytokines, including interferon-gamma (IFN-γ) and Interleukin-10 (IL-10), which exert inhibitory effects on tumors and leukemia, among other conditions. Vδ2T cells are the predominant γδT cell subset in peripheral circulation, accounting for approximately 50% to 75% of the total peripheral γδT cells, and mainly expressing the Vγ9 chain [17] . Vδ2T cells can therefore be separated into two subpopulations: Vγ9 + Vδ2 + and Vγ9 - Vδ2 + [18] . Vγ9 + Vδ2 + cells constitute a significant majority in the peripheral blood [12] . Vδ2T cells are present in various locations within the human body. For instance, McCarthy et al. [8] demonstrated that pro-inflammatory Vδ2T cells populate the mucosa of the human colon and small intestine. In contrast to Vδ1T cells and Vδ2T cells, Vδ3T cells are enriched in the liver and intestinal epithelium and are rare in the peripheral blood. 2.2 γδT cell differentiation γδT cells differentiate to produce different cytokines and are classified into two main effector subpopulations based on the specific cytokines produced [5] . IFN-γ-producing γδT cells, also known as γδT1 cells, secrete IFN-γ, which is involved in pathogen clearance and anti-tumour responses. IL-17-producing cells, called γδT17 cells, express Toll-like receptors TLR1 and TLR2 and can interact directly with certain pathogens [19] . γδT17 cells reside predominantly in barriers, including the lungs, skin, vagina, and mouth, and can be recirculated in specific pathological conditions, such as infections and cancers. During inflammation, γδT17 cells are mainly activated by IL-1β and IL-23 production by dendritic cells (DCs) and macrophages [20] . IL-17A production is associated with the clearance of extracellular bacteria and fungi [21] . The migratory ability of γδT17 cells is modulated by chemokine receptors, specifically CCR6 during homeostasis and CCR2 during inflammation [22] . Some studies have suggested that γδT can be differentiated into γδT1 cells, γδT17 cells and regulatory γδT (γδTreg) cells [23] . Treg cells are a subpopulation of T cells that control autoimmunity and play an important role in immune diseases. Among them, γδTreg cells can be polarized by transforming growth factor-β1 (TGF-β1) and exhibit a more potent immunosuppressive impact than CD4 + regulatory T cells (Treg) in colorectal cancer [24] . 2.3 γδT cell function γδT cells are highly plastic and perform diverse functions, including immunomodulation, tissue repair, and cytotoxicity. As a result, γδT cells are implicated in various diseases, not only with the ability to recognize and eliminate tumour cells, but also in processes such as chronic inflammation and damage repair. γδT cells have been shown to induce anti-tumour effects [25] . They exhibit MHC-independent tumour-directed cytotoxicity and can identify cancer cells through multiple mechanisms [26] . Activated γδT cells secrete granzyme, perforin, IFN-γ, and tumour necrosis factor-α (TNF-α) to exert cytotoxic effects and regulate immune responses, including DCs and αβT cells to kill tumour cells [18] . γδT cells also play a significant role in inflammatory responses. For example, in skin inflammation, γδT cells are involved in maintaining skin integrity under homeostatic conditions and are activated when injury or inflammation occurs. Activated γδT cells initially secrete chemokines that recruit inflammatory cells, such as neutrophils and macrophages. They subsequently secrete cytokines, including insulin-like Growth Factor 1(IGF-1), keratinocyte growth factor(KGF), and IL-17, to regulate inflammation and re-epithelialization [27] . In the later stages of inflammation, persistently activated γδT cells induce a sustained inflammatory microenvironment involved in chronic wound healing [28] . Intestinal γδT cells, which produce cytokines such as IL-17 and INF-γ and interact with other lymphocytes, also play an important role in the inflammatory response in the colon [29] . 3. γδT cells and immunity γδT cells have a unique immune function, serving as a link between innate and adaptive immunity [14] , and they can quickly respond to various pathogens for early immune defence. Evidence is accumulating that γδT cells are significant in the coordination of innate and acquired immune responses and are involved in a variety of autoimmune diseases. 3.1 The role of γδT cells in innate immunity In innate immunity, the main cells involved during infection or inflammation include dendritic cells, macrophages, and neutrophils [1, 30] . γδT cells can directly recognize proteins and non-peptide ligands without MHC restriction, thus they become key components in the first line of defence against infection and wound healing [31] . γδT cells are activated by stimulated epithelial cells or DCs, leading to the rapid release of chemokines for neutrophils, notably IL-17, which serves as the primary attractant for neutrophils [32] . Macrophages are an important component of innate immunity. γδT cells can also produce macrophage chemokines such as CCL2, which regulate the regulation of macrophage homeostasis and recruitment [32, 33] . Thus, γδT cells are significant contributors to innate immunity. 3.2 The role of γδT cells in acquired immunity In acquired immunity, γδT cells play multiple roles: Antigen presentation: The human Vδ2T cell subset, which functions as APCs, is able to present antigens to CD4 + T cells and CD8 + T cells to initiate adaptive responses [34] . Coordination of the immune response: γδT can interact with a wide range of immune cells, facilitating the transition from an innate to an adaptive immune response [35] . γδT cells can interact with αβT cells, for example, Vγ9Vδ2T cells are activated to produce IFN-γ, which promotes the production of IL-12 by DCs through a positive feedback pathway mediated by IL-12 and IFN-γ, thereby enhancing Th1-type αβT cell differentiation [8, 32] . Additionally, γδT cells can also provide assistance to B cells. Activated Vγ9Vδ2T cells can produce large amounts of CXCL13 to regulate B cells within lymphoid tissue follicles [32, 36] . Immunomodulation: Activated γδT cells can inhibit Treg cell proliferation while producing IL-10 and TGF-β to exert immunomodulatory effects [23] . Notably, γδTreg cells show increased expression of Treg markers CD39 and CD73, demonstrating immunosuppressive capacity [37] . 3.3 The role of γδT cells in autoimmune diseases γδT cells play important roles in multiple autoimmune diseases through their unique immune functions. In rheumatoid arthritis, γδT cells can cellularly recognize antigens presented by synovial fibroblasts and secrete cytokines including IL-17, IL-4 and IFN-γ, which exacerbate joint inflammation [38] . Several studies have found significant increases in γδT cell subsets (Vδ1T, Vδ2T, Vδ3T) in peripheral blood and liver in patients with autoimmune liver disease, supporting the involvement of these subsets in autoimmunity [39] . In psoriasis, a highly proliferative autoimmune disease, abnormally activated γδT cells secrete cytokines including IL-17 and IFN-γ, which may exacerbate the disease [33] . IBD is an autoimmune disease with abnormal activation of intestinal immunity. γδT cells secrete different cytokines that exhibit functions similar to those of Th1, Th17 and Treg, playing important roles in intestinal immunity regulation. 4 γδT cells and IBD IBD is a chronic, intermittently recurrent intestinal inflammatory disorder [1] . It causes tissue damage due to innate immune dysfunction coupled with dysregulated adaptive immune activation, collectively driving inflammatory response. Extensive infiltration of T cells into the intestinal mucosa is an important hallmark of IBD. During active disease states, abnormally activated macrophages and neutrophils secrete inflammatory cytokines such as IL1, IL6, IL-17and IFN-γ, activate DCs, secrete TGF-β, TNF-α, and other cytokines, which facilitate the differentiation of T cells into Th1, Th17, and Treg cells, which are implicated in intestinal mucosal injury [40] . γδT cells are special types of T cells located in the intestinal epithelium and lamina propria. They are key immune mediators in gut-associated lymphoid tissue [41] . These cells possess the capacity to produce diverse cytokines and chemokines and exhibit multiple functions similar to those of Th1, Th17, Treg and other cells. The intestinal epithelium consists of a single cell layer that separates the intestinal lumen from the lamina propria below [42] . Intraepithelial lymphocytes (IELs) are located within the epithelial cell layer of the mucosa and are primarily T lymphocytes in the intestinal region. γδ intraepithelial lymphocytes (γδIELs) are extensively present in the intestinal epithelium, constituting 60% of IELs in the small intestine, predominantly consisting of Vδ1T cells [8] . They migrate between the intestinal epithelium and the basal lamina of the small intestine [43] , and they are regulated by microorganisms present on the surface of the intestinal epithelium [44] . γδIELs are essential for immune homeostasis in the intestinal region, maintaining the integrity of the intestinal barrier, limiting microbiome translocation, responding to antigenic invasion, and repairing tissue damage [45, 46] . γδIELs also have a controversial role in the intestinal tract, with some γδIELs being able to secrete cytokines that protect intestinal epithelial cells, while others may have detrimental effects on the intestinal tract [47] . The lamina propria beneath the intestinal epithelium contains a significant quantity of immune cells including B cells, T cells, macrophages, and DCs [42] . Among them, γδT accounts for approximately 10% of lymphocytes. During inflammation, γδT cells can be recruited from the periphery to the lamina propria to promote inflammation. However, there is still disagreement as to whether the role of γδT in IBD is beneficial or detrimental. While some experimental models demonstrate a protective role for γδT cells in colitis, others suggest that expansion and activation of γδT cells may result in the exacerbation of colitis [48] . This review systematically summarizes the changes in the number of γδT cells in IBD, their types, the main cytokines they secrete and related treatments, as is shown in Figure 2. 4.1 Numbers of γδT cells in IBD The number of γδT cells also changes during IBD, but studies in recent years have found conflicting changes in the number of γδT cells. This paper summarizes the quantitative changes in IBD, as shown in Table 1. Some studies have found increased numbers of γδT cells in patients with IBD. Giacomelli R et al. [49] found that IBD was associated with an increase in γδT cells in the peripheral blood. Bucht A et al. [50] observed a significant increase in the proportion of γδT cells in the peripheral blood of patients with CD compared to healthy individuals. McVay LD et al. [51] found increased numbers of γδT cells in areas of inflammation and tissue damage in most patients with IBD. Tuchiyayt T et al. [52] found that the absolute number of γδT cells in the peripheral blood was increased in patients with IBD, mainly due to an increase in the subpopulation of Vδ1Vγ8T cells. Manner et al. [48] found that the number of γδT cells was increased in regions of intestinal inflammation in individuals with UC and CD, indicating that γδT cells may contribute to IBD. However, some studies have found a decrease in the number of γδT in IBD. Lee HB et al. [53] found that the percentage of γδT cells in intestinal mucosal lymphocytes in CD was significantly lower than in normal controls. Andreu-Ballester et al. [54] found that lymphocyte populations were reduced in the peripheral blood of patients with CD, with the greatest reduction in the γδT subpopulation. Gryglewski et al. [29] found a notable decrease in γδT cells in the peripheral blood of colitis patients, which may be due to the migration of these cells to the peritoneal lymphoid organs, where they likely participate in disease progression. Increased expression of the γδT cell intestinal homing receptor CCR9 in CD and UC may reflect the recruitment of γδT cells from the circulation to the inflamed skin and intestine [48] . 4.2 Types of γδT cells in IBD intestinal tissue With the increasing research related to γδT cells, several studies have identified the major cellular types of γδT in IBD. This paper summarizes the relevant clinical studies in recent years, as shown in Table 2. Tsuchiya et al. [52] found an increase in the Vδ1Vγ8T cells in the peripheral blood of patients with UC or CD. Kadivar et al. [55] found that the enrichment of CD8αβ + γδT cells in the gut was significantly greater than that of the overall γδT cell population. Additionally, CD8αβ + γδT cells were found to produce IFN-γ and TNF-α, which are key cytokines in the cell-mediated immune response. Presti et al. [56] found a reduction in tissue Vδ1T cells and an elevation in Vδ2T cells in the intestine of IBD patients. Libera et al. [57] found that compared to healthy individuals, IBD patients had a lower frequency of gut-derived CD39 + γδT cells. Gryglewski et al. [29] found that worsening of UC resulted in a decrease in the proportion of peripheral blood γδT cells and the number of γδT cells expressing CD25, CD54, and CD62L increased. Dart et al. [58] found that the CD103 + Vγ4T cells were susceptible to IBD-related cytokines, showing significant reductions and dysregulation in numbers in both CD and UC. Zhu et al. [59] found that intestinal CD8 + γδT cells were reduced in patients with active CD, and dysfunction of these cells correlated with increasing disease activity. New types of γδT cells have been identified not only in clinical experiments but also in some mouse models of colitis. For example, Do et al. [60] identified a cell type, CD103 + α4β7γδT cell, that may play a pro-inflammatory role in generating Th1 or Th17 effector cells, thereby exacerbating colitis. 4.3 Cytokines secreted by γδT in IBD γδT cells secrete various cytokines and have a significant role in the progression of IBD. This paper summarizes the main cytokines secreted by γδT cells in IBD. 4.3.1 IL-17 IL-17 is a pro-inflammatory cytokine primarily produced by Th17 cells and is significant in the mediation of immune injury [61] . In addition to Th17 cells, γδT cells serve as the primary source of IL-17 [61, 62] , including IL-17A and IL-17F [63] . IL-17 helps maintain intestinal epithelial integrity, and under homeostatic conditions, the innate production of IL-17 on the epithelial surface is mainly from γδT17 cells [64] . Under inflammatory conditions, human γδT cells may also acquire the capacity to produce IL-17 [22] . γδT17 cells are crucial in infections and autoimmune diseases [14] . They can secrete various cytokines [61] , and facilitate the recruitment of neutrophils and monocytes to exacerbate inflammatory responses [33] . In IBD patients, Th17 cells specifically produce IL-17, and γδT cells also secrete large amounts of IL17, which influences intestinal immunity [14] . Additionally, IL-17 produced by γδT cells promotes the induction of Th17 differentiation [65, 66] . The role of IL-17 in IBD remains contentious. Some studies have suggested that IL-17A exerts a pro-inflammatory effect in acute trinitro-benzene-sulfonate-induced colitis. Elevated amounts of IL-17 produced by Th17 cells, ILC3 and γδT cells in the colonic mucosa may exacerbate the development of chronic colonic inflammation [61] . Conversely, other studies have shown that IL-17A has a protective effect and maintains barrier function by modulating the tight junction protein occludin [67] , which acts in a protective manner in dextran sulfate sodium salt (DSS) induced colitis [68] . There are also relevant studies on the pathways of IL-17 in inflammation. For example, the proximal tyrosine kinase Syk is essential for γδT cell stereotyping and γδT17 cell differentiation [69] . Among them, the Syk/PI3K pathway is a key determinant of pro-inflammatory γδT cell differentiation [70] , suggesting that the Syk-mediated signalling pathway may be a potential therapeutic target for γδT17-dependent inflammatory diseases [69] . However, the specific mechanism of IL-17 requires further investigation. 4.3.2 IFN-γ INF-γ is a cytokine that is crucial in various immune responses, primarily produced by NK cells, Th1 cells, and other immune cells [71] . In the inflamed mucosa of CD patients, γδT cells are also a major source of IFN-γ [51] . Mucosal lamina propria Vδ2T cells are highly sensitive to microbial phosphoantigens, and in response to stimulation, Vδ2T cells in inflamed tissues exhibit altered surface phenotypes and produce the pro-inflammatory cytokine IFN-γ. This cytokine enhances Th1 polarization of colonic αβT cells and exacerbates intestinal inflammation [8, 72] . 4.3.3 TNF-α TNF-α is an inflammatory cytokine primarily secreted by macrophages and Th1 cells implicated in inflammation and several autoimmune diseases [73] . Elevated levels of TNF-α and IFN-γ are observed in the mucosa of patients with IBD [55] . Vδ2T cells are increased in IBD and contribute to increased TNF-α, and Vδ2T cell frequency correlates with IBD severity [57, 74] . McCarthy et al. [75] found that TNF-α production by mucosal Vδ2T cells was increased in CD and that blocking retinoic acid receptor-α signalling by drugs reduced TNF-α production by Vδ2T cells. In summary, the main cytokines secreted by γδT cells in IBD are IL-17, IFN-γ, and TNF-α. The secretion capacity of different γδT cell subpopulations also varies, with Vδ2T cells producing more IL-17, IFN-γ, and TNF-α compared to Vδ1T cells [76] . Additionally, the same γδT-cell subsets differ in their secretory capacity across the disease course of IBD. with tissue Vδ1T cells from patients with early and late IBD expressing similar levels of IFN-γ, but Vδ1T cells from patients with early IBD tended to express more TNF-α, and Vδ1T cells from patients with late IBD expressed more IL-17 [56] . Other cytokines, such as TGF-β, are also relevant. TGF-β signalling in γδIELs is essential for intestinal homeostasis and control of DSS-induced colitis, which may worsen as a result of TGF-β depletion [45] . Human γδT cells express the chemokine receptor CXCR3, which interacts with the chemokines CXCL9, CXCL10, and CXCL11 produced by localized inflammatory cells, thereby facilitating the recruitment of γδT cells to the intestinal mucosa during inflammatory bowel conditions [48] . 4.4 Deficiency of γδT cells in IBD Although the role of γδT cells in IBD remains contentious, deficiency of γδT cells has been shown to exacerbate intestinal inflammation and death in different types of animal models of IBD [77] . Several studies have shown that DSS-induced colitis is more severe in the absence of γδT cells [78] . Mouse TCRδ-/-mice lacking γδT cells are more susceptible to DSS-induced colitis and have a reduced ability to repair damaged epithelial cells [47] . Knockdown of occludin in mouse γδIELs in vivo leads to defective γδT cell motility within the intestinal epithelium, which reduces the number of intestinal γδIELs [79] . It is evident that γδT cell depletion or deficiency may lead to increased inflammation. In addition, γδT cells are involved in maintaining other intestinal features that regulate barrier function. In TCRδ-/- mice, the number of mucus-secreting cup cells is significantly reduced and the length of intestinal crypts is shortened [47] . Thus, γδT cells are also important for the maintenance of the intestinal barrier and recovery after injury. 4.5 γδT cell-based therapy in IBD Treatment of disease based on γδT cells has emerged as a promising therapeutic tool and has been investigated in a number of immunological diseases. For example, 3H-1,2-dithiazole-3-thione attenuates skin thickening and flaking by inhibiting IL-17A-secreting γδT cells in imiquimod-induced psoriasis mice [80] . L-theanine improves the function of γδT cells within the immune system, affects cytokine secretion, and serves an immunomodulatory role in inflammation [81] . There is a growing body of research being conducted on IBD. For example, in a phase 2 trial, monoclonal antibody administration that blocked NKG2D was present not only in NKT cells but also in γδT cells, showing promising results in CD [40] . Lactobacillus brevis DM9218 activates γδT17 cells through TLR2 expression in the colon, resulting in beneficial effects for colitis [44] . Selenium may prevent DSS-induced chronic colitis by increasing the number of Th1, Th17 and γδT cell populations and suppressing the release of pro-inflammatory cytokines [82] . Bacterial alliances significantly promoted the expansion of γδT17 cells in the lamina propria of the colon, which helped to restore the intestinal flora and improve mucosal barrier function in mice with colitis [65] .Vδ2T cells exhibit a pro-inflammatory function in CD, and their ability to be modified by dietary vitamin metabolites and ablated by azathioprine therapy may contribute to the resolution of intestinal inflammation [75] . In addition, research based on the modulation of γδT cells by herbal compounds and their extracts for the treatment of immune disorders is also on the rise. Xiaoyinfang is an evidence-based TCM formula developed to reduce psoriasis-like skin inflammation by inhibiting the polarization of dermal IL-17-producing γδT17 cells [83] . As for the treatment of IBD, radicchioflavin (LFS-01), an active ingredient of the TCM Lysergic acid, can regulate the skewed intestinal flora and enhance the production of γδ17T cells through Lactobacillus expansion, which is beneficial to DSS-induced colitis mice [44] . Therefore, the treatment of IBD based on the regulation of γδT cells has significant therapeutic potential, which deserves to be further explored to offer new approaches to IBD treatment. 5. Conclusions and prospects Although constituting a minor proportion of the T cells, γδT cells have been increasingly recognized as critical modulators of immune responses. γδT cells are the guardians of epithelial cells against trauma, infection and other injuries [47] . Emerging evidences demonstrate that γδT cells play an essential role in IBD, and preliminary studies have investigated the changes in the number of γδT cells, their main types, and the cytokines they secrete in IBD. Accumulating studies have attempted to further explore the specific processes by which γδT cells function in IBD. However, current findings are limited, particularly regarding the function of different γδT cell subpopulations. Notably, conflicting observations persist across studies, some reports indicate potentially protective functions in colitis models, while others have shown to be detrimental. Therefore, the relationship between γδT cells and IBD should be studied in depth in the future, and the distribution of γδT cells in peripheral blood and intestinal mucosa, the types of γδT cells in inflammatory and non-inflammatory mucosa, and the difference between γδT cells and cytokines secreted by other T cells can be studied in IBD. These help to better define the specific role of γδT cells in IBD in the pathogenesis and clinical symptoms of IBD and provide strategies for γδT cell-based IBD therapy. 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Giacomelli R [49] IBD Blood Increase 1994 Bucht A [50] CD Blood Increase 1995 McVay LD [51] IBD Intestinal mucosa Increase 1997 Tsuchiyayt T [52] IBD Peripheral blood Increase 2003 Manner [48] UC and CD Intestinal mucosa Increase 2012 Lee HB [53] CD Intestinal mucosa Decrease 1997 Andreu-Ballester [54] CD Peripheral blood Decrease 2011 Gryglewski [29] UC Peripheral blood Decrease 2021 Tsuchiya [52] UC or CD Blood Vδ1/Vγ8 T 2003 Increased Vδ1/Vγ8T cell subsets Kadivar [55] IBD Intestinal mucosa CD8αβ + γδT 2016 CD8αβ + γ T cells were significantly more enriched than γδT cells Presti [56] IBD Intestinal mucosa Vδ1T/Vδ2T 2019 Decrease in γV1T cells, increase in γV2T cells Libera [57] IBD Intestinal mucosa CD39 + γδT 2020 Decreased frequency of CD39 + γδT cells Gryglewski [29] UC Peripheral blood γδT 2021 Increased γδT cells expressing CD25, CD54 and CD62L Dart [58] UC and CD Intestinal mucosa CD103 + Vγ4T 2023 Dysregulation of CD103 + Vγ4 T cell numbers Zhu [59] CD Intestinal mucosa CD8 + γδT 2024 Decreased number and dysfunction of CD8 + δT Table 2. Types of γδT cells in IBD. Figure legends Figure 1. The structure, differentiation and function of γδT cells. Figure 2. γδT and IBD. The intestinal epithelium consists of a single cell layer in which γδIELs are distributed, and the lamina propria contains a large number of immune cells, such as T and B cells, macrophages, and dendritic cells, as well as a small number of γδT cells. In IBD, γδT cell numbers and types undergo changes, and these cells secrete cytokines such as IL-17, IFN-γ, and TNF-α. When γδT cells are deficient, intestinal inflammation is exacerbated. Therapies based on γδT cells can alleviate inflammation. Supplementary Material File (figure 1.tif) Download 57.52 MB File (figure 2.tif) Download 39.94 MB Information & Authors Information Version history V1 Version 1 11 March 2025 Peer review timeline Published Immunology Version of Record 25 Jun 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Immunology Keywords autoimmunity autoinflammatory disease inflammation t cell Authors Affiliations Baoqing Xu First Teaching Hospital of Tianjin University of Traditional Chinese Medicine View all articles by this author Jianbin Ji First Teaching Hospital of Tianjin University of Traditional Chinese Medicine View all articles by this author Lingling Ma First Teaching Hospital of Tianjin University of Traditional Chinese Medicine View all articles by this author Chunyan Wang First Teaching Hospital of Tianjin University of Traditional Chinese Medicine View all articles by this author Lianjing Pang First Teaching Hospital of Tianjin University of Traditional Chinese Medicine View all articles by this author QingChao Song First Teaching Hospital of Tianjin University of Traditional Chinese Medicine View all articles by this author Yang Liu First Teaching Hospital of Tianjin University of Traditional Chinese Medicine View all articles by this author Zhenghua Zhou First Teaching Hospital of Tianjin University of Traditional Chinese Medicine View all articles by this author Fanfan Qu [email protected] First Teaching Hospital of Tianjin University of Traditional Chinese Medicine View all articles by this author Metrics & Citations Metrics Article Usage 319 views 268 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Baoqing Xu, Jianbin Ji, Lingling Ma, et al. γδT cells in IBD: beneficial or detrimental?. 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