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Therapeutic effectiveness of Dau-UC7. A, Dau-UC7, DauH57, Dau-IgG, or Dau was injected at tumor sites on days 4, 5, and 6 after i.p. inoculation of MM2. Untreated MM2-bearing mice were used as a control. B, Dau-UC7, Dau-H57, or Dau-IgG was injected at tumor sites on days 4, 5, and 6 after s.c. inoculation of MH134. Untreated MH134-bearing mice were used as a control. Data are representative of two independent experiments.
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It has been demonstrated that γδ T cells accumulating in early tumor lesions and those purified from spleen cells of tumor-bearing mice attenuate the activity of CTLs and NK cells. We, therefore, investigated whether depletion of γδ T cells from early lesions of tumors results in restoration of CTL and NK cell activities and subsequent regression o...
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... above finding raised the possibility that intralesional injections of Dau-UC7 restore the function of tumor-specific CTLs and NK cells by depressing T cells and result in subsequent inhibition of tumor development. When Dau-UC7 was intralesionally given on days 4, 5, and 6 after i.p. inoculation of MM2, the MM2 tumor regressed completely (Figs. 3A and 4), and the MM2 regressor mice subsequently survived for over 10 mo. On the other hand, the growth of MH134 tumor was also suppressed by the administra- tion of Dau-UC7 on days 4, 5, and 6 after s.c. inoculation of tumor cells, although the MH134 tumor gradually developed thereafter, and all of the mice died within 2 mo after the tumor ...
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... and the MM2 regressor mice subsequently survived for over 10 mo. On the other hand, the growth of MH134 tumor was also suppressed by the administra- tion of Dau-UC7 on days 4, 5, and 6 after s.c. inoculation of tumor cells, although the MH134 tumor gradually developed thereafter, and all of the mice died within 2 mo after the tumor inoculation (Fig. 3B). In contrast, there were no therapeutic effects when Dau- UC7 was administered intralesionally on days 15, 16, and 17 after MM2 or MH134 inoculation (data not shown). This is consistent with our previous finding that T cells function as suppressor cells in an early tumor formation (19). No attenuation of tumors was found when Dau-IgG ...
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... Dau- UC7 was administered intralesionally on days 15, 16, and 17 after MM2 or MH134 inoculation (data not shown). This is consistent with our previous finding that T cells function as suppressor cells in an early tumor formation (19). No attenuation of tumors was found when Dau-IgG or daunomycin alone was used at the same concentration as Dau-UC7 (Figs. 3 and 4). A weak inhibition of MM2 tumor progression was found in mice treated with Dau- H57 on days 4, 5, and 6 after i.p. MM2 inoculation, while such an inhibition of tumor growth was not observed in MH134-bearing mice (Fig. 3B). Subsequently, the mice died within 25 days fol- lowing vigorous progression of MM2 (Fig. 3A). These results raise ...
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... (19). No attenuation of tumors was found when Dau-IgG or daunomycin alone was used at the same concentration as Dau-UC7 (Figs. 3 and 4). A weak inhibition of MM2 tumor progression was found in mice treated with Dau- H57 on days 4, 5, and 6 after i.p. MM2 inoculation, while such an inhibition of tumor growth was not observed in MH134-bearing mice (Fig. 3B). Subsequently, the mice died within 25 days fol- lowing vigorous progression of MM2 (Fig. 3A). These results raise the possibility that a portion of T cell populations modestly inhibit antitumor cytotoxic cells in early formation of MM2 le- sions. This may be in accordance with our previous finding that early-appearing Th2-T cells ...
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... concentration as Dau-UC7 (Figs. 3 and 4). A weak inhibition of MM2 tumor progression was found in mice treated with Dau- H57 on days 4, 5, and 6 after i.p. MM2 inoculation, while such an inhibition of tumor growth was not observed in MH134-bearing mice (Fig. 3B). Subsequently, the mice died within 25 days fol- lowing vigorous progression of MM2 (Fig. 3A). These results raise the possibility that a portion of T cell populations modestly inhibit antitumor cytotoxic cells in early formation of MM2 le- sions. This may be in accordance with our previous finding that early-appearing Th2-T cells exhibit suppressive features against NK activities (19). Results from the in vivo studies ...
Citations
... Notably, the suppressive capacity of γδ T cells can be reversed by TLR8 engagement. In certain experimental settings, the suppressive capacity of γδ T cells was at least partially dependent on IL-10 and TGF-β signaling [46,47]. Additionally, it has been demonstrated that γδ T cell-derived galectin-1 induced by MDSCs can cause a significant decrease in antitumor immunity and increased tumor growth [48]. ...
T cells are a subset of T cells that are characterized by the expression of a TCR‐γδ instead of a TCR‐αβ. Despite being outnumbered by their αβ T cell counterpart in many tissues, studies from the last 20 years underline their important and non‐redundant roles in tumor and metastasis development. However, whether a γδ T cell exerts pro‐ or antitumorigenic effects seems to depend on a variety of factors, many of them still incompletely understood today. In this review, we summarize mechanisms by which γδ T cells exert these seemingly contradictory effector functions in mice and humans. Furthermore, we discuss the current view on inducing and inhibiting factors of γδ T cells during cancer development.
... Similar mechanisms of immunosuppression by TGF-β were shown in γδ T cells and iNKT cells, in which TGF-β also contributed to the induction of IL-17-producing human Vγ9Vδ2 + T cells 47 and to both the development and peripheral responsiveness of type 17 iNKT cells 155 . In addition to their response to TGF-β-signalling in the TME, ILTCs such as γδ T and MAIT cells can secrete TGF-β in vivo contributing to an immunosuppressive feedforward loop [156][157][158] . Although the relative contribution of ILC-derived and ILTC-derived TGF-β to immune evasion in cancer remains to be determined, these findings provide further insights on how the ILC and ILTC network could act as signal amplifiers in the hostile TME. ...
Immunotherapies targeting conventional T cells have revolutionized systemic treatment for many cancers, yet only a subset of patients benefit from these approaches. A better understanding of the complex immune microenvironment of tumours is needed to design the next generation of immunotherapeutics. Innate lymphoid cells (ILCs) and innate-like T cells (ILTCs) are abundant, tissue-resident lymphocytes that have recently been shown to have critical roles in many types of cancers. ILCs and ILTCs rapidly respond to changes in their surrounding environment and act as the first responders to bridge innate and adaptive immunity. This places ILCs and ILTCs as pivotal orchestrators of the final antitumour immune response. In this Review, we outline hallmarks of ILCs and ILTCs and discuss their emerging role in antitumour immunity, as well as the pathophysiological adaptations leading to their pro-tumorigenic function. We explore the pleiotropic, in parts redundant and sometimes opposing, mechanisms that underlie the delicate interplay between the different subsets of ILCs and ILTCs. Finally, we highlight their role in amplifying and complementing conventional T cell functions and summarize immunotherapeutic strategies for targeting ILCs and ILTCs in cancer.
... Indeed, it has been observed that treatment with the anti-γδ TCR mAb clone UC7-13D5 led to a slight and short-term increase in the percentage of αβ T lymphocytes, which, however, returned to normal levels within the first days [76]. Furthermore, changes in IFNγ production or in the activity of cytotoxic T cells and natural killer cells observed in other studies indicate that γδ T cell depletion may have led to similar side effects also in our experimental setting [77,78]. Finally, it is known that the binding of anti-γδ TCR mAb to γδ T cells leads to the formation of antigen-antibody complexes, resulting in the production and release of cytokines via activation of the complement system and further binding to Fcγ receptors on immune cells [79][80][81][82]. ...
γδ T cells, a small subset of T cells in blood, play a substantial role in influencing immunoregulatory and inflammatory processes. The functional impact of γδ T cells on angiogenesis in ischemic muscle tissue has never been reported and is the topic of the present work. Femoral artery ligation (FAL) was used to induce angiogenesis in the lower leg of γδ T cell depleted mice and wildtype and isotype antibody-treated control groups. Gastrocnemius muscle tissue was harvested 3 and 7 days after FAL and assessed using (immuno-)histological analyses. Hematoxylin and Eosin staining showed an increased area of tissue damage in γδ T cell depleted mice 7 days after FAL. Impaired angiogenesis was demonstrated by lower capillary to muscle fiber ratio and decreased number of proliferating endothelial cells (CD31+/BrdU+). γδ T cell depleted mice showed an increased number of total leukocytes (CD45+), neutrophils (MPO+) and neutrophil extracellular traps (NETs) (MPO+/CitH3+), without changes in the neutrophils to NETs ratio. Moreover, the depletion resulted in a higher macrophage count (DAPI/CD68+) caused by an increase in inflammatory M1-like macrophages (CD68+/MRC1−). Altogether, we show that depletion of γδ T cells leads to increased accumulation of leukocytes and M1-like macrophages, along with impaired angiogenesis.
... Les LT- semblent également capables de produire des cytokines suppressives telles que l'IL-10 et le TGF- (pour transforming growth factor), comme cela a été observé pour des LT- infiltrant des tumeurs mammaires murines (Seo et al., 1999). Ces propriétés suppressives ont pu être induites in vitro en réponse au TGF- (Kang et al., 2009). ...
Les lymphocytes T (LT) CD8 innés sont une population de LT non conventionnels récemment décrits dans le laboratoire. On les qualifie de « non conventionnels » car ils possèdent des caractéristiques de l’immunité acquise (facteur de transcription Eomesodermine et phénotype T mémoire) mais aussi de l’immunité innée (récepteurs des cellules NK, réponse à une stimulation cytokinique de type inné). Les fonctions de ces cellules sont encore peu connues, même s’il existe un faisceau d’argument en faveur de leur implication dans l’immunité anti-infectieuse et anti-tumorale.Il a été décrit que l’immuno-sénescence et/ou la stimulation antigénique chronique (induite par exemple par les infections virales chroniques au cytomégalovirus ou CMV) entraîne(nt) l’expression de marqueurs NK par les LT. Ce phénotype se rapproche donc de celui de nos cellules d’intérêt. Pour étudier l’effet de la stimulation antigénique chronique sur le compartiment LT CD8, et spécialement sa composante innée, nous avons choisi comme modèle la transplantation d’organe. Dans ce domaine, la recherche s’intéresse aux populations immunitaires susceptibles de jouer un rôle dans la tolérance ou le rejet du greffon. Parmi elles, les LT CD8 innés méritent une attention spéciale, ceci du fait de leurs fonctions innées effectrices/cytotoxiques. Nous avons présumé leur (re)programmation par la stimulation antigénique chronique (du greffon et/ou virale) pendant la transplantation. Cette hypothèse a été testée à partir d’une cohorte de patients transplantés rénaux depuis plus de dix ans, sous traitement immunosuppresseur minimisé (ciclosporine A (CsA) en monothérapie), en l’absence de signe clinico-biologique de rejet. Notre travail a d’abord permis de révéler dans les LT CD8 innés issus des donneurs sains (DS) un phénotype sénescent accentué (fréquence de cellules CD27(-)CD28(-) augmentée) que les LT CD8 conventionnels. En outre, la fréquence de cette population T innée, contrairement aux LT CD8 conventionnels, ne corrélait pas avec l’âge. Dans la cohorte de patients transplantés, nous avons observé une augmentation de la fréquence des LT CD8 innés, accompagnée d’un phénotype sénescent et effecteur terminal (CD45RA(+)CCR7(-)) exacerbé, comparativement aux cellules des DS. Les patients présentant une sérologie positive pour le CMV avaient un phénotype sénescent accru par rapport aux patients présentant une sérologie négative.En altérant la signalisation du TCR, le traitement immunosuppresseur CsA pourrait faciliter la (re)programmation des LT CD8 en faveur de leur versant inné. En accord avec cette hypothèse, une modélisation in vitro des effets de la CsA sur les LT CD8 provenant de DS en présence d’une stimulation du TCR et d’IL-15 a permis de documenter une augmentation du pool de LT CD8 innés au détriment du pool de LT naïfs, laquelle est accompagnée d’une valorisation de leurs fonctions (production innée d’IFN-γ). A l’inverse, chez les patients, les LT CD8 innés étaient dysfonctionnels, avec une production innée d’IFN-γ diminuée qui pourrait résulter de leur expression membranaire diminuée du récepteur de l’IL-15, cytokine indispensable aux LT CD8 innés. Ce dysfonctionnement, qui ne peut être attribué à un programme d’exhaustion ni être relié à un antécédent de cancer, pose la question du rôle de la stimulation allo-spécifique chronique. De façon générale, ce travail suggère que le contexte d’allogreffe rénale entraîne une reprogrammation et un phénotype de type « vieillissement » des LT CD8 innés, liés au moins en partie au traitement immunosuppresseur. Cette hypothèse devra être confortée par une analyse fine de l’allo-spécificité des LT CD8 innés dirigée contre le greffon.
... CD8 + Treg cells secrete either TGF-β or IL-10 [37,38]. Furthermore, antigen-activated CD8 + γδ T cells can prevent insulin-dependent diabetes in mice [39], and IL-10-and TGF-β-producing regulatory γδ T cells can suppress the antitumor activity of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells [40]. In addition, natural killer T (NKT) cells can secrete regulatory cytokines, including IL-10 [41]. ...
Immune homeostasis is a tightly regulated system that is critical for defense against invasion by foreign pathogens and protection from self-reactivity for the survival of an individual. How the defects in this system might result in autoimmunity is discussed in this review. Reduced lymphocyte number, termed lymphopenia, can mediate lymphopenia-induced proliferation (LIP) to maintain peripheral lymphocyte numbers. LIP not only occurs in normal physiological conditions but also correlates with autoimmunity. Of note, lymphopenia is also a typical marker of immune aging, consistent with the fact that not only the autoimmunity increases in the elderly, but also autoimmune diseases (ADs) show characteristics of immune aging. Here, we discuss the types and rates of LIP in normal and autoimmune conditions, as well as the coronavirus disease 2019 in the context of LIP. Importantly, although the causative role of LIP has been demonstrated in the development of type 1 diabetes and rheumatoid arthritis, a two-hit model has suggested that the factors other than lymphopenia are required to mediate the loss of control over homeostasis to result in ADs. Interestingly, these factors may be, if not totally, related to the function/number of regulatory T cells which are key modulators to protect from self-reactivity. In this review, we summarize the important roles of lymphopenia/LIP and the Treg cells in various autoimmune conditions, thereby highlighting them as key therapeutic targets for autoimmunity treatments.
... Accumulating data about the regulatory function of γδT cells has been also published. It has been shown that decidual and intestinal γδT cells produce high levels of TGFβ and IL-10 and can inhibit cytotoxic T-cell responses and induce a tolerogenic environment in case of pregnancy (beneficial effect) or case of tumors (harmful effect) [32][33][34][35][36]. Thus, quite successfully γδT cells can either boost or dampen the immune responses [37]. ...
In this chapter, human unconventional γδT lymphocytes and their major subsets will be described with emphasis on their role in the immune protection in general and in the context of pregnancy. In particular, I will outline the main events and immune cells at the maternal-fetal interface during implantation/early pregnancy in humans focusing on the recent advances of the proportion, phenotype, and TRG/TRD repertoires of maternal γδT cells at the place of maternal-fetal contact and drawing comparisons with their peripheral blood counterparts. “Crossing” maternal-fetal interface I will highlight some new data on the fetal γδT cells and their effector phenotype and phosphopathogens reactivity, acquired in utero.
... In mice, IL-10-producing γδ T cells have been identified in tumors. In a breast cancer model, supernatant from infiltrating γδ T cells suppresses the proliferation of anti-tumor CTLs in an IL-10dependent manner (83). In a syngeneic model of OVA-expressing EL4 tumors (lymphoma), IL-10-producing γδ T cells suppress the CD8-dependent anti-tumor response, and their depletion significantly reduces tumor growth (84). ...
The tumor immune microenvironment contributes to tumor initiation, progression and response to therapy. Among the immune cell subsets that play a role in the tumor microenvironment, innate-like T cells that express T cell receptors composed of γ and δ chains (γδ T cells) are of particular interest. Indeed, γδ T cells contribute to the immune response against many cancers, notably through their powerful effector functions that lead to the elimination of tumor cells and the recruitment of other immune cells. However, their presence in the tumor microenvironment has been associated with poor prognosis in various solid cancers (breast, colon and pancreatic cancer), suggesting that γδ T cells also display pro-tumor activities. In this review, we outline the current evidences of γδ T cell pro-tumor functions in human cancer. We also discuss the factors that favor γδ T cell polarization toward a pro-tumoral phenotype, the characteristics and functions of such cells, and the impact of pro-tumor subsets on γδ T cell-based therapies.
... These types are depending on IL-10 and tumour growth factor-β production for their suppressive activity (13,14). Also γδ T cell and CD8 + T cell populations contain suppressive subsets, but their specific roles in regulating the immune system have yet to be identified (15)(16)(17)(18)(19). ...
Regulatory T cells (Tregs) have a prominent role in the control of immune homeostasis. Pharmacological impact on their activity or balance with effector T cells could contribute to (impaired) clinical responses or adverse events. Monitoring treatment-related effects on T cell subsets may therefore be part of (pre-)clinical studies for medicinal products. However, the extent of immune monitoring performed in studies for marketing authorisation and the degree of correspondence with data available in the public domain is not known. We evaluated the presence of T cell immunomonitoring in 46 registration dossiers of monoclonal antibodies indicated for immune-related disorders and published scientific papers. We found that the depth of Treg analysis in registration dossiers was rather small. Nevertheless, data on treatment-related Treg effects are available in public academia-driven studies (post-registration) and suggest that Tregs may act as a biomarker for clinical responses. However, public data are fragmented and obtained with heterogeneity of experimental approaches from a diversity of species and tissues. To reveal the potential added value of T cell (and particular Treg) evaluation in (pre-)clinical studies, more cell-specific data should be acquired, at least for medicinal products with an immunomodulatory mechanism. Therefore, extensive analysis of T cell subset contribution to clinical responses and the relevance of treatment-induced changes in their levels is needed. Preferably, industry and academia should work together to obtain these data in a standardised manner and to enrich our knowledge about T cell activity in disease pathogenesis and therapies. This will ultimately elucidate the necessity of T cell subset monitoring in the therapeutic benefit-risk assessment.
... In contrast, stimulation of γδ T cells in the presence of TGF-β leads to the induction of FOXP3 expressing γδ T cells with suppressive phenotype (165,166). These appropriately called regulatory γδ T cells have been shown to exert their suppressive function through the production of IL-10 and TGF-β to inhibit T cell activation and proliferation (165)(166)(167)(168). ...
The distinction between innate and adaptive immunity is one of the basic tenets of immunology. The co-operation between these two arms of the immune system is a major determinant of the resistance or susceptibility of the host following pathogen invasion. Hence, this interactive co-operation between cells of the innate and adaptive immunity is of significant interest to immunologists. The sub-population of CD4⁺ T cells with regulatory phenotype (regulatory T cells; Tregs), which constitute a part of the adaptive immune system, have been widely implicated in the regulation of the immune system and maintenance of immune homeostasis. In the last two decades, there has been an explosion in research describing the role of Tregs and their relevance in several immunopathologies ranging from inflammation to cancer. The majority of these studies focus on the role of Tregs on the cells of the adaptive immune system. Recently, there is significant interest in the role of Tregs on cells of the innate immune system. In this review, we examine the literature on the role of Tregs in immunology. Specifically, we focus on the emerging knowledge of Treg interaction with dendritic cells, macrophages, neutrophils, and γδ T cells. We highlight this interaction as an important link between innate and adaptive immune systems which also indicate the far-reaching role of Tregs in the regulation of immune responses and maintenance of self-tolerance and immune homeostasis.
... Contrarily, IL-10 has anti-inflammatory potential (Saraiva & O'garra, 2010). Production of immunosuppressive cytokines, such as IL-10 and TGF-β that can be produced by several tumors can increase tumor progression by suppressing the adaptive antitumor immune responses (Seo, Tokura, Takigawa, & Egawa, 1999). A study on glioblastoma showed that TGF-β can downregulate NKG2D expression on the NK cells (Crane et al., 2009). ...
Natural killer (NK) cells play an essential role in the immune response to infections, inflammations, and malignancies. Recent studies suggest that NK cell surface receptors and cytokines are the key points of the disease development and protection. We hypothesized that the interactions between NK cell receptors and targeted cells construct an eventual niche, and this niche has an eventual profile in various autoimmune diseases and cancers. The NK cells preactivated with cytokines, such as interleukin‐2 (IL‐2), IL‐12, IL‐15, and IL‐18 can have higher cytotoxicity; however, the toxic side effect of IL‐2 should be considered. The vicissitudes of NK cell profile and its receptors obey the environmental communications and cell interactions. Our vision around the NK cells as an immune axis remained dual, and we still cannot judge the immune responses based on the NK cell flip‐flop. A design of eventual niche to monitor the NK cell and targeted cell interaction is needed to strengthen our ability in diagnosis and treatment approaches based on the NK cells. Here, we have reviewed the shifts in the NK cells and their surface receptors in autoimmune diseases, solid tumors, and leukemia, and also discussed the effective chemokines that affect NK cell activation and proliferation. The main aim of this review is to present a broader vision of the NK cell changes in autoimmune disease and cancers.
