The tumour-protective ability of mucins against the host immune r

The tumour-protective ability of mucins against the host immune response

is embedded on its structural peculiarity. The interested readers are directed to refer excellent reviews on mucin structural biology [29, 30] for a comprehensive account on this subject. Mucins can be both immunostimulatory and immunosuppressive in their effects. MUC-1, for example, is a highly immunogenic tumour-associated antigen (TAA) that provides a unique immune system access to the MUC-1 over expressing breast, pancreas and ovarian carcinomas [31]. If poorly glycosylated on its VNTR [32], it elicits humoral [33] and cellular immune responses [34], and the major epitope recognized by the antibodies is the PDTRPAP sequence with its o-glycosylation on its threonine residues [35, 36]. Interestingly, antigen processing of MUC-1 by dendritic cells (DC) or in human immunoproteasomes in vitro retains its o-linked glycans on its repeat domains. Its JNK inhibitor cost 20 amino acid tandem repeat (TR) posses three specific cleavage sites, being processed by human cathepsin L in low-density endosomes in a manner that is sensitive to o-glycosylation positions. Proteolysis of Thr-3-Ser-4 peptide bond in the TR does not occur if either amino acid is o-glycosylated, and this MK-1775 manufacturer masking of cleavage site is responsible for inertness of tumour-associated MUC-1 glycoforms to effective DC processing [37]. Further, it has been found that the

processed SAPDT(GalNAc)RPAPG decameric glycopeptide containing a single sugar (GalNAc) binds strongly Liothyronine Sodium to MHC class I allele HLA A*0201, whereas the same sequence glycosylated with the disaccharide Gal-GalNAc does not bind at all [38]. Processed MUC-1 TRs can use GalNAc to anchor on to the c-pocket of HLA class I (H-2 kb) molecule, and the number of

anchors subsequently influences the affinity with which MUC-1 is presented on to the MHC class I [39]. Low-affinity binding of the 9-mer MUC-1 peptide sequences (APDTRPA and STAPPAHGV) on to the HLA-A2 is partly due to the lack of high-affinity consensus motif and to the under glycosylation [40], and only HLA-A11 binding is close to the immunogenic value [41]. Nevertheless, cytotoxic T lymphocytes (CTLs) generated against it are highly active and could lyse the human breast cancer cells expressing MUC-1 [40]. Breast cancer cells therefore escape from autologous CTLs by expressing MUC-1-related antigenic epitopes more weakly or by modulating its antigenicity [42]. Complete loss of MUC-1 is also observed in some breast tumour cell lines that are unresponsive or resistant to CTL cytotoxicity and characterized with antitumor immunity [42]. Conversely, downregulation or loss of HLA class I expression in MUC-1 or c – erbB2 overexpressing NSCLC cells confer poor prognosis of the disease [43] and the mice lacking MHC- Class I made weak CTL response [44]. Dendritic cells (DCs) form a crucial link between innate and adaptive immunity leading to specific T cell activation.

2a,b), supports this hypothesis In migrating neutrophils, eosino

2a,b), supports this hypothesis. In migrating neutrophils, eosinophils, fibroblasts,

and MDCK-F cells, it has been demonstrated that increases in [Ca2+]i were localized to the rear part of the cells [23]. Calcium-activated K+ channels localized to the rear part of the cell play an important role in cell migration since it has been shown that the migratory activity of MDCK-F cells was sensitive to the inhibition of KCa3.1 [23]. Accordingly, as shown in the present study the LPS-induced global cell swelling, Ca2+ accumulation and migration were reduced in KCa3.1-deficient BMDCs when compared to WT DCs (Fig. 2) suggesting that LPS-induced migration of DCs might involve the activation of KCa3.1. However, as we mentioned above, we cannot exclude that LPS-induced DC swelling occurs independently Maraviroc of DC migration. We observed that the reduction of LPS-induced swelling at early time points was only moderate in

KCa3.1-deficient BMDCs (Fig. 2a) when compared to TLR4-deficient BMDCs (Fig. 1a). In DC, it has been demonstrated previously that LPS induces cell swelling by transient activation of the Na+/H+ exchanger [13]. Hence, in KCa3.1-deficient BMDCs an LPS/TLR4-induced activation of the Na+/H+ exchanger operating in parallel to the Cl−/HCO3 exchanger might occur leading to the entry of NaCl together with osmotically obliged water [19]. As shown in Figure 2c, the baseline migratory activity of non-unstimulated KCa3.1-deficient buy PD-0332991 BMDCs was comparatively high when compared to WT DCs. We assumed that possible differences in cell size could be causative for this phenomenon. Analysis

of the forward scatter as a measure of cell size of non-stimulated BMDCs revealed an enhanced cell size of KCa3.1-deficient DCs when compared to WT DCs (data not shown) which might contribute to the high migratory activity of KCa3.1-deficient DCs. In order to test whether the altered migratory capacities resulted from changes in the expression of CCR7, WT and KCa3.1-deficient BMDCs were analyzed by flow Rucaparib mouse cytometry. CCR7 expression on WT and KCa3.1−/− DCs kept in medium for 4 hr was 18.1 ± 6.1 and 21.8 ± 8.2%, respectively (data not shown). Treatment with LPS (500 ng/mL) for 4 hr caused an increase in CCR7 expression in both cell types (27.2 ± 2.8 and 34.0 ± 3.0%, respectively) (data not shown). Altogether, expression of CCR7 by unstimulated and stimulated DCs was slightly enhanced in KCa3.1-deficient cells when compared to WT DCs. Hence, although CCR7 in part might contribute to DC migration, factors other than CCR7 expression like possible compensating activities of other ion channels could be causative for the high migratory activity of untreated KCa3.1−/− DCs (Fig. 2c). Moreover, since the CCR7 expression on KCa3.1−/− DCs was enhanced after LPS treatment, the low migratory activity of these cells (Fig. 2c) cannot be attributed to the changes in CCR7 expression.

At 7

days after implantation, cells double-positive for G

At 7

days after implantation, cells double-positive for GFP and myoglobin and cells double-positive for GFP and SMA are present within the wound region as isolated cells that are not in physical contact with each other. In contrast, by 14 days the GFP and myoglobin double-positive cells are in contact with each other and with non-GFP expressing striated cells derived from uninjured surrounding tissues. Similarly, the GFP and SMA double-positive cells also contact each other and non-GFP expressing smooth muscle cells. The association of these cells forms higher order layered muscle structures within the urethral sphincters. check details Furthermore, within the developing musculature, there are blood vessel walls containing smooth muscle cells that are double-positive for GFP and SMA. These results suggest that the striated muscle

and smooth muscle cells derived from implanted bone marrow-derived cells may advance the reconstruction of muscle tissues and vascular components to support them. At 7 days after cell implantation, a few of the GFP-labeled implanted cells are simultaneously positive for Pax7 (Fig. 4e), suggesting that they have myoblast properties. In the development process to mature muscle, Pax7 acts as transcription factor, and satellite cells and myoblasts both express Pax7, but mature muscle cells do not. Currently we cannot determine if the cells expressing both GFP and Pax7 are presumptive satellite cells or myoblasts. Nevertheless, the implanted cells clearly follow a development process that leads to the differentiation of striated or smooth muscle cells. The number of the cells expressing both GFP and Pax7 on day 14 is distinctly higher than on day

7 (Fig. 4f). Myoblasts properly differentiate into striated or smooth muscle cells according to surrounding environment.2 The greater number of Pax7 cells on day 14 compared to day 7 suggests that the formation rate of differentiated muscle cells may have decreased or even stopped. This suggests that the process of new striated and smooth muscle cell differentiation Resveratrol is under some type of intrinsic regulation. Understanding the controls for differentiation of the implanted cells is very important for further development of regenerative medicine. While the details of this regulation are currently unknown, it is clear that the presence of the myoblasts in the regenerated region may have important long-term significance. In the event that the newly differentiated striated and/or smooth muscle tissues and structures spontaneously regress or are lost for other reasons, the presence of the myoblasts could ensure the replacement of the lost cells. Thus, the effects of treatments may be maintained for long periods of time. To develop regenerative medicine, we must investigate and provide various cell sources that are best suited to the health conditions and lifestyles of our patients.

Therefore, it was concluded that the use of CoxAbic® as a method

Therefore, it was concluded that the use of CoxAbic® as a method of vaccination offers at least the same level of protection and economic advantage as those commonly accepted and used in the poultry market. Further evidence of the effectiveness of the maternal immunization approach in the field was obtained in Thailand and South Africa. In a challenge trial in Thailand, three groups of vaccinated birds – CoxAbic®, a commercial live vaccine and salinomycin treated MK-1775 purchase – were challenged with 60 000 virulent E. tenella oocysts orally. Lesion scores between the three flock groups revealed that the CoxAbic® vaccinated groups had the lowest lesion score (<0·5) at 24, 30 and 35 days of age. In contrast, live

vaccine treated flocks had a lesion score >2 during the same period, whilst salinomycin treated flocks peaked at 30 days of age with a score >2·5, but recovered to ∼1·0 at day 35 (72), again confirming the effectiveness of vaccination with CoxAbic®. These results demonstrated that maternal immunization with gametocyte antigens provides the potential for controlling coccidiosis under different rearing conditions in various climates and environmental surroundings. The basis of control, rather than eradication, means that both sexual and asexual stage protective immunity develops in the birds.

Importantly, several recent studies demonstrated the conserved and functional importance of the two gametocyte antigens, Gam56 and Gam82, and explained why their inclusion in the vaccine formula confers protection against a range of Eimeria species (76). Concurrent to development of CoxAbic®, studies were conducted to characterize the Gam56 and Gam82 antigens that are the main components of the vaccine. Initial studies showed that Gam56 and Gam82 are glycoproteins (77) and further immunofluorescence studies

localized these antigens to the wall-forming bodies of the macrogametocyte and in the oocyst wall (78). These two antigens were identified as key players in the formation of the oocyst wall (54,69,79,80). The oocyst wall, which facilitates the transmission of Eimeria by protecting pentoxifylline the parasite when it is in the outside world, originates from the fusion of specialized organelles – wall-forming bodies (WFB’s) – found in the macrogametocytes of Eimeria (78). During maturation of the macrogametocyte, the WFB’s align beneath the cell surface before degranulating and releasing Gam56 and Gam82 (Figure 1b). The proteins, and/or truncated versions thereof, are then believed to cross-link via dityrosine bonds to form the resilient wall structure (81). The inclusion of these proteins in CoxAbic® means that the stimulated antibodies probably interfere with the formation of cross-link’s between the proteins (Figure 1b), and therefore, prevent effective transmission by interrupting oocyst wall formation (72,82).

Next, T-cell proliferation and polarization were investigated by

Next, T-cell proliferation and polarization were investigated by mixed

leucocyte reaction to determine whether the effect MK-1775 solubility dmso induced by IFN-β on A. fumigatus-infected DC maturation resulted in an enhanced capacity in promoting the expansion of Th1-oriented CD4+ T cells. As shown in Fig. 5(a), A. fumigatus-infected DCs induced the proliferation of naive allogeneic cord blood CD4+ T cells, which was not significantly modified when infected DCs were primed with IFN-β. Interestingly, IFN-β priming of A. fumigatus-infected DCs highly enhanced the production of IFN-γ, as observed by the analysis of supernatants obtained from mixed leucocyte reaction cultures (Fig. 5b). Conversely, no induction of IL-4 was found when T cells were co-cultured with A. fumigatus-stimulated DCs in the presence or absence of IFN-β (data not shown). Type I IFNs, originally identified for their Gemcitabine datasheet ability to induce cellular resistance to viral infections, are key immunomodulators of the innate and

adaptive immune responses.29 By acting on DC differentiation and maturation, these cytokines can induce cross-priming of CD8 T cells19 and stimulate a Th1-oriented T-cell response.21,22 Accordingly, our recent findings showed that IFN-β potentiates DC immunological functions following bacillus Calmette–Guérin infection, pointing to the importance of IFN-β in promoting a protective Th1 immune response against Mycobacterium tuberculosis.30 Based on this evidence, the use of type I IFN constitutes a promising immunotherapy for infectious diseases.13,15 Invasive aspergillosis is a serious opportunistic fungal infection in immunocompromised hosts. Advances

in more potent and less toxic antifungal agents have reduced DOK2 the mortality rate of IA and represent a promising area of research and development to cure invasive fungal infections. Moreover, novel strategies for immunotherapy and vaccine are also currently designed on the knowledge of the immunopathogenesis of fungal infections.31 Although clinical evidence points to a crucial role for the Th1 reactivity in the control of IA, more recently regulatory T cells and Th17 cells could display important functions in the scenario of the immune response against A. fumigatus.32 However, if the role of IL-17-producing T cells in protection versus pathology in fungal infections is still controversial,33–35 it is generally accepted that a defective differentiation of regulatory T cells may cause an unacceptable level of tissue damage.3 Several studies in human and murine models have, however, confirmed the central role of IFN-γ released by interstitial lung lymphocytes in controlling IA through the stimulation of phagocytosis and intracellular antifungal killing mechanisms of neutrophils and macrophages.

Indeed, recent studies described the significance of such interac

Indeed, recent studies described the significance of such interactions [29]; that plasma membrane phosphoinositides play a central role in regulating the organization and dynamics of the actin cytoskeleton by acting as platforms for protein recruitment, triggering signaling cascades and directly regulating the activities

of actin-binding proteins. One could speculate that the ζ chain could serve as an adapter molecule linking between the plasma membrane and the actin microfilaments. Assessing the potential synergy of both interactions is expected to open new and important directions toward selleck chemicals the understanding of T-cell activation processes. T cells devoid of cska-TCRs resemble normal T cells treated with agents that disrupt actin polymerization [7, 30], and cells that were mutated

in signal transduction proteins as VAV and ITK, which are also involved in actin-based cytoskeleton rearrangement upon TCR-mediated activation [4, 31]. Interestingly, the features of T cells lacking cska-TCRs, due to the expression of ζ mutated in its two RRR motifs, were similar to those observed in cells isolated from a chronic inflammatory Doxorubicin environment characterized by immunosuppression and a massive ζ downregulation, while the remaining TCR subunits are expressed normally [32]. Our preliminary results indicate that under such conditions the cska-TCRs are the primary receptors dramatically downregulated, resulting in impaired TCR-mediated TCR clustering and IS formation, leading to T-cell dysfunction

(data not shown). These initial data support the in vivo significant role of the cska-TCRs in T-cell activation processes. Further studies are required to explore this phenomenon due to its critical implication in various chronic inflammatory pathologies as cancer, autoimmune, and infectious diseases, all characterized by partial or severe T-cell immunosuppression [33]. In conclusion, our novel results suggest a model (Fig. 4) for the unique role of the cska-TCRs in resting and activated T cells. The cska ζ via the two positively charged motifs enables learn more maintenance of a physical link between plasma membrane TCRs and actin in resting T cells, which is absent in the MUT cells (Fig. 4A). This linkage, allows an immediate interaction of TCRs with the cytoskeleton upon Ag recognition. During immediate stages of activation (Fig. 4B), cska-TCRs in the WT cells play a dual role: (i) inducing physical changes that affect reorganization of both the cytoskeleton (actin bundling) and the plasma membrane profile (TCR clustering and IS formation), and (ii) initiating immediate signaling events, directly affecting the cytoskeleton. In contrast, these events are absent from the T cells expressing the MUT ζ. At a later stage of activation (Fig.

The low-potassium lettuce maintains the nutritional value for ele

The low-potassium lettuce maintains the nutritional value for elements other than potassium. Therefore, the consumption of low-potassium

lettuce may inhibit the advancement this website of atherosclerosis and renal function deterioration. Basic and clinical studies will be conducted in the future to examine the safety and efficacy of low-potassium vegetables and fruits. KAZAMA JUNICHIRO J1, MATSUO KOJI1, YAMAMOTO SUGURU1, KAWAMURA KAZUKO1, WAKASUGI MINAKO1, NARITA ICHIEI1, TOKUMOTO AKIHIDE2 1Division of ClinicalNephrology, Niigata University; 2Kamifukubara Medical Clinic Introduction: Trabecullar bone connectivity is one of the components of bone quality. Today, renal osteodystrophy (ROD) is diagnosed with a tetracycline AZD5363 labelling-based 2-demensional bone histomorphometry, which has been developed mainly for the purpose of assessing bone metabolism, whereas its ability in evaluating bone structural properties is limited. On the other hand, a newly developed X-ray image based

3-dimensional morphometry is a reliable device to assess the structural properties, but not capable for assessing bone metabolism. Although a previous 2-dimensional study reported the possible influence of bone turnover on cancellous bone structure, this finding has not been confirmed in the 3-dimensional level. Methods: Forty-eight dialysis patients who underwent iliac bone biopsy examination were subjected for the analyses. Conventional tetracycline labelling-based 2-dimensional bone histomorphometry was performed on the processed sections. Serial tomographic images Ponatinib order of remained bone samples were obtained with a micro-computed tomographic system and the 3-dimensional structure was reconstructed. Quantitative image analyses were performed in the virtual 3-dimensional space. Following morphometric parameters

were obtained; Bone Formation Rate (BFR/BS) as the indicator of bone turnover, Bone Volume (BV/TV), Trabecular Thickness (TbTh) and Trabecular Number (TbN) as the indicators of cancellous bone amount, Fractal Dimension (FD), Structure Model Index (SMI) and Trabecular Bone Pattern Factor (TBPf) as the indicators of cancellous bone surface property and Marrow Space Star Volume (V*m), Connectivity Density (Conn D) and Number of Nodes (N.Nd/TV) as direct indicators of trabecular bone connectivity. Results: BFR/BS showed significant negative correlations with both SMI and TBPf, but not with BV/TV, TbTh, TbN, Df, V*m, Conn D or N.Nd/TV, respectively. Conclusion: Increased bone turnover was associated with complicated uneven surface pattern in cancellous bones. However, such surface pattern changes did not affect trabecular bone amount or connectivity. Thus, bone turnover seemed to have little potential to affect bone quality through modifying cancellous bone structural properties.

, 2004; Mulvey et al , 2005; David et al , 2008; Van De Griend et

, 2004; Mulvey et al., 2005; David et al., 2008; Van De Griend et al., 2009). Recent studies show that USA400 can account for over 98% of MRSA infections in northern Canada (Golding et al., 2011) and has been implicated in isolated see more MRSA disease in southern Europe (Vignaroli, 2009; Neocleous et al., 2010). However, about 10 years ago, a new source of CA-MRSA arose from one of the ‘traditional’ virulent CCs, CC8. Descending from a USA500

clone through acquisition of various MGEs (Robinson & Enright, 2003; Li et al., 2009), USA300 became the dominant CA-MRSA clone in US (Moran et al., 2006; Hulten et al., 2010; Talan et al., 2011), effectively replacing USA400 clones in most regions (Como-Sabetti et al., 2009; Simor et al., 2010), and has also been isolated from patients in Canada and Mexico (Nichol Depsipeptide cell line et al., 2011; Velazquez-Meza et al., 2011).

The explosion of USA300 CA-MRSA across North America resulted from a very recent clonal expansion of a successful CA-MRSA clone as demonstrated by very low sequence divergence among geographically distinct USA300 isolates (Kennedy et al., 2008). Given the occurrence of multiple CA-MRSA clones in the population, a formal definition was put forth by the Center for Disease Control and Prevention for CA-MRSA disease as that which is contracted within 48 h of hospital admission by patients not having recently undergone surgery, hemodialysis, prolonged hospitalization, Non-specific serine/threonine protein kinase catheterization, or MRSA colonization (Morrison et al., 2006). Currently in the US, MRSA disease fitting these criteria is almost always caused by USA300 clones, followed by USA400 and occasionally USA1000 and USA1100 (Talan et al., 2011). To complicate matters further, USA300 clones have recently been implicated in causing significant HA-MRSA disease (Popovich et al., 2008; Jenkins et al., 2009; Moore et al., 2009; Hulten et al., 2010), blurring the lines between the two disease

onset environments (Popovich et al., 2008; Jenkins et al., 2009; Moore et al., 2009; Hulten et al., 2010). In some studies, USA300 accounted for at least half of hospital-acquired MRSA infections (Popovich et al., 2008; Hulten et al., 2010). Thus, USA300 represents a highly successful S. aureus clone that emerged in the community and quickly spread throughout the North American continent to become the leading cause of MRSA infection even in healthcare settings. For now, USA300 seems to be primarily limited to North America, while in Europe, South America and Asia, CA-MRSA disease is dominated by divergent clones unrelated to CC8 (e.g. ST30, ST80 and ST59) (Deleo et al., 2010). Given the rapid and efficient transmissibility of USA300 in North America (Pan et al., 2005), it remains to be seen whether these clones will become the dominant source of MRSA disease worldwide. Animal models of S.

maxima APGA could induce cross-protection

to heterologous

maxima APGA could induce cross-protection

to heterologous species, E. tenella and E. acervulina, as well as E. maxima infections (68,69). At this point, it was believed that this cross-reactivity was most probably due to conserved epitopes of the major gametocyte antigens in the different species and, thus, led to the hypothesis that a vaccine of E. maxima gametocyte antigens could possibly be used to control coccidiosis caused by at least the three predominant Eimeria species. In floor pen maternal immunization trials, the resistance of chicks from APGA-immunized breeder hens was compared to that of hatchlings from control parent flocks by introducing oocysts to the pens via infection of ‘seeder’ birds infected with 50 oocysts of E. maxima, Acalabrutinib E. tenella and E. acervulina. Analogous to the laboratory trials, a reduction of 60–80% in oocyst shedding into the litter was observed; comparable to the reduction observed using coccidiostats (59). These selleck chemical trials were repeated three times under the same conditions, showing that there was an average reduction of 60–70% oocyst output in vaccinated groups up to 4–6 weeks in age (59,70). These results were encouraging, as they supported the idea that the highly conserved E. maxima antigens could provide good levels of protective immunity against at least three major species

that cause coccidiosis in broilers. Despite this, questions still remained about whether this vaccine could provide maternal protection against all Eimeria species (and strains) encountered in the field and if maternal immunity was applicable in controlling coccidiosis

within industry management schemes and climatic conditions. To further assess the efficacy of maternal immunization with APGA, testing was undertaken in a multi-centred, multinational field trial involving five countries from four different continents: Israel, Brazil, Argentina, South Africa and Thailand (71,72). The safety and immunogenicity of the vaccine in breeding hens were assessed on a large scale, with birds vaccinated twice prior to the start of their laying period (15 and 20 weeks respectively). Immunizations were found to have no deleterious effect on the hens (72): no adverse reactions; no damage at the site of injection; and no affect on hen mortality or on the number Amino acid of eggs produced (e.g., in the Argentine trials, 119 eggs were produced per immunized hen vs. 116 per control hen). In all four countries, IgG antibody titres remained at a presumptive protective level throughout the life of the laying hens. The maintenance of highly specific IgG antibody levels in vaccinated flocks is thought to be due to the boosting effect that is naturally acquired from exposure to infection with oocysts in the environment (72). It is even conceivable that maternal antibodies may increase due to this natural exposure. However, in the absence of immunization, these titres are variable and, therefore, do not necessarily provide protective levels of maternal immunity (72).

The ratio

The ratio of Teff cell counts versus CD11b+Gr1+ cell counts is increased about fivefold (53 ± 10, mean ± SEM) in the pancreas versus that in the tumor (9 ± 3, mean ± SEM) (Supporting Information Fig. 1). Moreover, the profile

of the populations differs in the healthy versus malignant tissues, in that the CD11b+Gr1+ cells in tumors had a much higher expression of CD11b. Treg-cell reconstitution did modestly increase circulating TGF-β1 levels in the tumor-bearing mice compared with that of control groups (Supporting information Fig. 2A). The elevated TGF-β1 level in blood circulation, however, had no apparent suppression on immunopathology in the pancreas, even though the increase in TGF-β1 was detectable before onset of immune damage in pancreas. Taken together, these results indicate that the insulinoma microenvironment, in combination with Poziotinib in vivo Treg cells and MDSC, effectively suppressed progression of autoimmunity-mediated damage of tumors by self-antigen-specific CD4+ Teff cells. This suppressive effect was local at the tumor site, with negligible systemic inhibition on the self-antigen-specific cells, as they retained their capacity in destroying nonmalignant target cells in the same animals. CD8+ T cells are potent effectors in antitumor immunity. Prompted by the observation of local suppression of autoimmune CD4+ Teff cells at the tumor site, we tested whether tumor microenvironment,

as opposed to healthy tissues, also suppress self-antigen-specific CD8+ Teff cells. The RIP-mOVA transgenic mice express an ovalbumin transgene in healthy pancreatic β cells [31]. Transgenic ovalbumin expression serves as a surrogate self antigen. These mice were used as a recipient for implanting E.G7-OVA lymphoma cells, which were stably transfected with the ovalbumin gene [32]. Adoptive transfer of activated CD8+ Teff cells from the OT1 transgenic Janus kinase (JAK) mice [33], which are specific to the ovalbumin antigen, completely destroyed the ovalbumin-expressing β cells and caused overt diabetes in the animals. However, lymphoma mass was only partially reduced, with limited inflammatory infiltration in the tumor tissue (Fig. 3).

Thus, the CD8+ Teff cells were inhibited at the tumor site in the lymphoma-bearing animals, without being substantially curtailed at the healthy tissue site expressing the same self-antigens. To further examine the pathophysiology of autoimmune mechanisms in antitumor immunity, we investigated the role of Treg cell-mediated suppression of self-antigen-specific Teff cells at tumor site in a setting that necessitated neither adoptive transfer of T cells nor lymphopenic conditions. The BDC2.5/NOD.Foxp3DTR model [34] was used. It carries a diphtheria toxin (DT) receptor transgene under the control of a Foxp3 promoter, enabling timed removal of 80–90% of Treg cells with a low dose of DT. NIT-1 tumor cells were injected into BDC2.5+ Foxp3DTR+ mice or littermate BDC2.5+Foxp3DTR− controls.