Alterations in regulatory T-cells: Rediscovered pathways in immunotoxicology

Laboratory of Toxicology, Department of Pharmacological Sciences, Università degli Studi di Milano, Italy.
Journal of Immunotoxicology (Impact Factor: 2.05). 08/2011; 8(4):251-7. DOI: 10.3109/1547691X.2011.598885
Source: PubMed


In addition to the effector T-cells subsets, T-cells can also differentiate into cells that play a suppressive or regulatory role in adaptive immune responses. The cell types currently identified as regulatory T-cells (T(regs)) include natural or thymic-derived T(regs), T-cells which express Foxp3(+)CD25(+)CD4(+) and can suppress immune responses to autoreactive T-cells, as well as inducible T(regs), that are generated from naïve T-cells in the periphery after interaction with antigens presented by dendritic cells. Inducible T(regs) include T(H)3 cells, T(r)1 cells, and Foxp3(+)-inducible T(regs). T(regs) have been shown to be critical in the maintenance of immune responses and T-cell homeostasis. These cells play an important role in suppressing responses to self-antigens and in controlling inappropriate responses to non-self-antigens, such as commensal bacteria or food in the gut. For example, depletion of CD4(+)CD25(+) T(regs) from mice resulted in the development of multi-organ autoimmune diseases. CD4(+)CD25(+) T(regs) and/or IL-10-producing T(r)1 cells are capable of suppressing or attenuating T(H)2 responses to allergens. Moreover, adoptive transfer of CD4(+)CD25(+) T(regs) from healthy to diseased animals resulted in the prevention or cure of certain autoimmune diseases, and was able to induce transplantation tolerance. Clinical improvement seen after allergen immunotherapy for allergic diseases such as rhinitis and asthma is associated with the induction of IL-10- and TGFβ-producing T(r)1 cells as well as FoxP3-expressing IL-10 T-cells, with resulting suppression of the T(H)2 cytokine milieu. Activation, expansion, or suppression of CD4(+)CD25(+) T(regs) in vivo by xenobiotics, including drugs, may therefore represent a relevant mechanism underlying immunotoxicity, including immunosuppression, allergic asthma, and autoimmune diseases.

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Available from: Emanuela Corsini
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    • "CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) are a unique subset of CD4+ T cells characterized by specific expression of CD25 (the α-chain of the receptor for interleukin-2) and the transcription factor forkhead box protein P3 (Foxp3) [4]. There is accumulating evidence that Tregs play an important role in the suppression of antitumor immune responses [5, 6]. Several recent studies have reported that increase population of Tregs in peripheral blood, draining lymph nodes, and tumor microenvironment in various cancer patients, including gastric, lung, breast, colorectal, and head and neck squamous cell carcinoma [7–10]. "
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    ABSTRACT: CD4+ CD25+ FoxP3+ T cells (Tregs) play an essential role in sustaining self-tolerance by negatively regulating immune responses. Increased frequencies of Tregs have been reported in a variety of human cancers. The aim of this study was to evaluate the prevalence of Tregs infiltration in the peripheral blood and regional lymph nodes during rat tongue carcinogenesis induced by 4-nitroquinoline-1-oxide (4NQO). Forty-eight Sprague-Dawley rats were divided into the control (n = 16) and experimental groups (n = 32) to which 4NQO in drinking water was administered. Flow cytometry was used to analyze the prevalence of Tregs in lymphocytes of peripheral blood and regional lymph nodes during 4NQO-induced rat tongue carcinogenesis. CD4+ CD25+ FoxP3+ cells were expressed as a percentage of the total CD4+ cells. The frequency of Tregs in peripheral blood from squamous cell carcinoma rats was significantly higher than controls (3.82 ± 0.62 versus 1.40 ± 0.31 %, P < 0.001). The proportion of Tregs was sequentially increased from moderate dysplasia to severe dysplasia and SCC (1.94 ± 0.72, 2.29 ± 0.82, and 3.82 ± 0.62 %, respectively). The frequency of Tregs in regional lymph nodes from squamous cell carcinoma rats was also significantly higher than normal rat mucosa (14.67 ± 3.09 versus 5.53 ± 2.07 %, P < 0.001). The percentage of Tregs was gradually increased in moderate dysplasia, severe dysplasia, and SCC groups (8.93 ± 1.74, 10.15 ± 0.86, 14.67 ± 3.09 %, respectively) as compared to control group (5.53 ± 2.07 %). Tregs in peripheral blood and lymph nodes were associated with disease progression during 4NQO-induced rat tongue carcinogenesis. This study indicated that the upregulation of Tregs might play important role during oral mucosa malignant transformation.
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    • "In a previous study in this laboratory, Bowers et al. [27] found that TCDD exposure at doses less than 40 µg/Kg had no significant effect on the course of disease in L. major-infected C57Bl/6 mice. Given the critical role of T cell responses in governing the outcome of leishmanial disease [8-13], and given the large number of studies demonstrating altered T cell responses in mice exposed to TCDD at doses lower than 40 µg/Kg [21-24], this finding could be considered unexpected. However, an earlier study by DeKrey and Kervkliet [48] found that TCDD at 40 µg/Kg was a threshold dose in C57Bl/6 mice for significant elevation of serum corticosterone levels, whereas significant suppression of an allograft rejection response in those same mice was evident at doses of TCDD as low as 5 µg/Kg. "
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    ABSTRACT: In a model of experimental cutaneous leishmaniasis, pre-exposure of Leishmania major-resistant mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor agonist, causes suppression of the protective anti-parasite T helper 1 response while paradoxically also reducing parasite burdens in those animals. In this study, we examined if TCDD exposure could also reduce parasite burdens in L. major-susceptible BALB/c mice. In the highest dose group (160 µg/Kg), TCDD treatment caused a significant reduction of parasite burdens by 10-fold after three weeks while also causing a significant lymphoid atrophy indicating suppression of the non-protective T helper 2 response. A dose-dependent delay of foot lesion progression was also observed such that lesion size in the highest dose group was less than half that of controls after 35 days of infection. Importantly, although TCDD exposure initially reduced disease severity and prolonged the course of disease by as much as three fold in some animals, this effect was transitory and TCDD did not induce resistance to L. major infection. Because TCDD exposure reduced L. major burdens in both resistant and susceptible mice, we hypothesized that TCDD reduces L. major burdens in mice by a mechanism that does not involve adaptive immunity. To test this, severe combined immunodeficient (SCID) mice were used. In mice infected with a moderate number of L. major (10,000), TCDD treatment caused a time- and dose-dependent decrease of parasite burdens by nearly 100-fold after six weeks in the highest dose group (200 µg/Kg). A significant and dose-dependent delay of foot lesion progression was also observed in these animals. These results indicate that TCDD exposure can reduce the severity of leishmanial disease in mice independent of adaptive immunity.
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    • "On the other hand, small molecular weight chemicals (<1000 Da) can form protein adducts, thus behaving as antigen, or by inducing cellular damage or altering protein processing, chemicals may unmask cryptic self-protein, leading to allergy or autoimmune disorders. Finally, breakdown of central tolerance of autoreactive B or T cells by immunosuppressive compounds , especially during in utero or early life exposure, has been related later in life to autoimmunity and abnormal hypersensitivity (Corsini et al., 2011; Fukuyama et al., 2011). Due to increased knowledge on the immune system, for a better understanding of the immunotoxic risk, studies on the molecular mechanisms of action of immunotoxic compounds are of great value. "
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    ABSTRACT: The immune system can be the target of many chemicals, with potentially severe adverse effects on the host's health. In Western countries pesticides, together with new and modified patterns of exposure to chemicals, have been implicated in the increasing prevalence of diseases associated with alterations of the immune response, such as hypersensitivity reactions, certain autoimmune diseases and cancers. Xenobiotics may initiate, facilitate or exacerbate pathological immune processes, resulting in immunotoxicity by induction of mutations in genes coding for immunoregulatory factors, modifying immune tolerance and activation pathways. The purpose of this article is to update the evidence of pesticide immunotoxicity. Even if experimental data as well as sporadic human studies indicate that some pesticides can affect the immune system, overall, existing epidemiological studies are inadequate to raise conclusions on the immunotoxic risk associated to pesticide exposure. The available studies on the effects of pesticides on human immune system have several limitations including poor indication on exposure levels, multiple chemical exposures, heterogeneity of the approach, and difficulty in giving a prognostic significance to the slight changes often observed. Further studies are necessary, and they should be preferably carried out through comparison of pre and post-exposure findings in the same group of subjects with a matched control group. Attempt should be made to define the prognostic significance of slight changes often observed. Animal and in vitro studies are also important and necessary to scientifically support epidemiological evidences on pesticide-induced immunotoxicity.
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