Regulatory T cells (Tregs) are indispensable for maintaining self-tolerance by suppressing conventional T cells. On the other hand, Tregs promote tumor growth by inhibiting anticancer immunity. In this study, we identified that Tregs increase the quorum of self-reactive CD8+ T cells required for the induction of experimental autoimmune diabetes in mice. Their major suppression mechanism is limiting available IL-2, an essential T-cell cytokine. Specifically, Tregs inhibit the formation of a previously uncharacterized subset of antigen-stimulated KLRK1+ IL-7R+ (KILR) CD8+ effector T cells, which are distinct from conventional effector CD8+ T cells. KILR CD8+ T cells show superior cell-killing abilities in vivo. The administration of agonistic IL-2 immunocomplexes phenocopies the absence of Tregs, i.e., it induces KILR CD8+ T cells, promotes autoimmunity, and enhances antitumor responses in mice. Counterparts of KILR CD8+ T cells were found in the human blood, revealing them as a potential target for immunotherapy.

As well as protecting us from invading pathogens, like bacteria or viruses, our immune system can also identify dangerous cells of our own that may cause the body harm, such as cancer cells. Once detected, a population of immune cells called cytotoxic T cells launch into action to kill the potentially harmful cell. However, sometimes the immune system makes mistakes and attacks healthy cells which it misidentifies as being dangerous, leading to autoimmune diseases. Special immune cells called T regulatory lymphocytes, or ‘Tregs’, can suppress the activity of cytotoxic T cells, preventing them from hurting the body’s own cells. While this can have a positive impact and reduce the effects of autoimmunity, Tregs can also make the immune system less responsive to cancer cells and allow tumors to grow. But how Tregs alter the behavior of cytotoxic T cells during autoimmune diseases and cancer is poorly understood. While multiple mechanisms have been proposed, none of these have been tested in living animal models of these diseases. To address this, Tsyklauri et al. studied Tregs in laboratory mice which had been modified to have autoimmune diabetes, which is when the body attacks the cells responsible for producing insulin. The experiments revealed that Tregs take up a critical signaling molecule called IL-2 which cytotoxic T cells need to survive and multiply. As a result, there is less IL-2 molecules available in the environment, inhibiting the cytotoxic T cells’ activity. Furthermore, if Tregs are absent and there is an excess of IL-2, this causes cytotoxic T cells to transition into a previously unknown subset of T cells with superior killing abilities. Tsyklauri et al. were able to replicate these findings in two different groups of laboratory mice which had been modified to have cancer. This suggests that Tregs suppress the immune response to cancer cells and prevent autoimmunity using the same mechanism. In the future, this work could help researchers to develop therapies that alter the behavior of cytotoxic T cells and/or Tregs to either counteract autoimmune diseases, or help the body fight off cancer.

• Klíčová slova
• IL-2, T cells, autoimmunity, cytotoxic, immune suppression, immunology, inflammation, mouse, regulatory T cells,
• MeSH
• CD8-pozitivní T-lymfocyty MeSH
• diabetes mellitus 1. typu * patologie   MeSH
• imunologická tolerance MeSH
• interleukin-2 MeSH
• lektinové receptory NK-buněk - podrodina K MeSH
• lidé MeSH
• myši MeSH
• receptory interleukinu-7 MeSH
• regulační T-lymfocyty * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• interleukin-2 MeSH
• KLRK1 protein, human MeSH Prohlížeč
• Klrk1 protein, mouse MeSH Prohlížeč
• lektinové receptory NK-buněk - podrodina K MeSH
• receptory interleukinu-7 MeSH

Adaptive immune responses are tailored to different types of pathogens through differentiation of naive CD4 T cells into functionally distinct subsets of effector T cells (T helper 1 (TH1), TH2, and TH17) defined by expression of the key transcription factors T-bet, GATA3, and RORγt, respectively. Regulatory T (Treg) cells comprise a distinct anti-inflammatory lineage specified by the X-linked transcription factor Foxp3 (refs 2, 3). Paradoxically, some activated Treg cells express the aforementioned effector CD4 T cell transcription factors, which have been suggested to provide Treg cells with enhanced suppressive capacity. Whether expression of these factors in Treg cells-as in effector T cells-is indicative of heterogeneity of functionally discrete and stable differentiation states, or conversely may be readily reversible, is unknown. Here we demonstrate that expression of the TH1-associated transcription factor T-bet in mouse Treg cells, induced at steady state and following infection, gradually becomes highly stable even under non-permissive conditions. Loss of function or elimination of T-bet-expressing Treg cells-but not of T-bet expression in Treg cells-resulted in severe TH1 autoimmunity. Conversely, following depletion of T-bet- Treg cells, the remaining T-bet+ cells specifically inhibited TH1 and CD8 T cell activation consistent with their co-localization with T-bet+ effector T cells. These results suggest that T-bet+ Treg cells have an essential immunosuppressive function and indicate that Treg cell functional heterogeneity is a critical feature of immunological tolerance.

• MeSH
• aktivace lymfocytů MeSH
• autoimunita imunologie   MeSH
• buňky Th17 cytologie   imunologie   MeSH
• CD8-pozitivní T-lymfocyty cytologie   imunologie   MeSH
• imunologická tolerance imunologie   MeSH
• myši MeSH
• proteiny T-boxu metabolismus   MeSH
• regulační T-lymfocyty cytologie   imunologie   metabolismus   MeSH
• separace buněk MeSH
• Th1 buňky cytologie   imunologie   MeSH
• Th2 buňky cytologie   imunologie   MeSH
• transkripční faktor T-bet MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• proteiny T-boxu MeSH
• transkripční faktor T-bet MeSH

Dysregulated systemic immune responses during infectious spondylodiscitis (IS) may impair microbial clearance and bone resorption. Therefore, the aim of the study was to examine whether circulating regulatory T cells (Tregs) are elevated during IS and whether their frequency is associated with alterations in T cells and the presence of markers of bone resorption in the blood. A total of 19 patients hospitalized with IS were enrolled in this prospective study. Blood specimens were obtained during hospitalization and 6 weeks and 3 months after discharge. Flow cytometric analysis of CD4 and CD8 T cell subsets, the percentage of Tregs and serum levels of collagen type I fragments (S-CrossLap) were performed. Out of 19 enrolled patients with IS, microbial etiology was confirmed in 15 (78.9%) patients. All patients were treated with antibiotics for a median of 42 days, and no therapy failure was observed. Next, a significant serum C-reactive protein (S-CRP) decrease during the follow-up was observed, whereas the frequencies of Tregs remained higher than those of controls at all-time points (p < 0.001). In addition, Tregs demonstrated a weak negative correlation with S-CRP and S-CrossLap levels were within the norm at all-time points. Circulating Tregs were elevated in patients with IS and this elevation persisted even after the completion of antibiotic therapy. Moreover, this elevation was not associated with treatment failure, altered T cells, or increased markers of bone resorption.

• Klíčová slova
• CrossLaps, Immune dysfunction, Infectious spondylodiscitis, Regulatory T cells,
• MeSH
• antibakteriální látky terapeutické užití   metabolismus   MeSH
• biologické markery metabolismus   MeSH
• discitida * diagnóza   farmakoterapie   metabolismus   MeSH
• lidé MeSH
• prospektivní studie MeSH
• regulační T-lymfocyty * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antibakteriální látky MeSH
• biologické markery MeSH

We evaluated dendritic cells (DC), regulatory T lymphocytes (Treg) and neutrophils in 37 patients with newly diagnosed renal cell carcinoma (RCC) in the tumor and peripheral blood (PB) and correlated these parameters with tumor staging (early-T1, 2, late-T3, 4 and metastatic disease). The number of myeloid and plasmacytoid DC in blood of RCC patients was higher than in healthy controls. The percentage of myeloid dendritic cells (mDC) from CD45+ cells in tumors was higher in comparison with peripheral blood irrespective of disease stage. Higher percentage of these cells expressed a maturation marker in the periphery in the early stage (CD83 expressing cells). The number of plasmacytoid dendritic cells (pDC) in PB was similar in both early and late stage groups, but the early group displayed a significantly higher percentage of pDC in tumor cell suspension. Neutrophil counts in the peripheral blood of RCC patients were higher than in healthy controls, but the counts in both tumor stage groups were similar. The proportion of neutrophils from CD45+ cells was higher in late stage tumors. Higher percentage of Treg from CD4+ cells was detected in renal carcinoma tissue in comparison to PB with no difference between stages of the disease. Our results reflect the complex interplay between various cells of the immune system and the tumor microenvironment. Activation of dendritic cell subpopulations at early stages of the disease course is counterbalanced by the early appearance of T regulatory cells both in the periphery and tumor tissue. Later stages are characterized by the accumulation of neutrophils in the tumor. Appropriate timing of anticancer strategies, especially immunotherapy, should take these dynamics of the immune response in RCC patients into account.

• Klíčová slova
• CTL, DC, Dendritic cells, NK, Neutrophils, PB, RCC, Regulatory T cells, Renal cell carcinoma, TIN, Treg, Tumor infiltration, cytotoxic T lymphocytes, dendritic cells, mDC, myeloid dendritic cells, natural killer, pDC, peripheral blood, plasmacytoid dendritic cells, regulatory T lymphocytes, renal cell carcinoma, tumor infiltrating neutrophils,
• MeSH
• aktivace lymfocytů imunologie   MeSH
• antigen CD83 MeSH
• antigeny CD45 metabolismus   MeSH
• CD antigeny metabolismus   MeSH
• dendritické buňky imunologie   MeSH
• dospělí MeSH
• imunoglobuliny metabolismus   MeSH
• karcinom z renálních buněk imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové glykoproteiny metabolismus   MeSH
• myeloidní buňky imunologie   MeSH
• nádorové mikroprostředí imunologie   MeSH
• nádory ledvin imunologie   MeSH
• neutrofily imunologie   MeSH
• počet lymfocytů MeSH
• regulační T-lymfocyty imunologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD45 MeSH
• CD antigeny MeSH
• imunoglobuliny MeSH
• membránové glykoproteiny MeSH
• PTPRC protein, human MeSH Prohlížeč

Regulatory T cells have been well described and the factors regulating their development and function have been identified. Recently, a growing body of evidence has documented the existence of interleukin-10 (IL-10) -producing B cells, which are called regulatory B10 cells. These cells attenuate autoimmune, inflammatory and transplantation reactions, and the main mechanism of their inhibitory action is the production of IL-10. We show that the production of IL-10 by lipopolysaccharide-stimulated B cells is significantly enhanced by IL-12 and interferon-γ and negatively regulated by IL-21 and transforming growth factor-β. In addition, exogenous IL-10 also inhibits B-cell proliferation and the expression of the IL-10 gene in lipopolysaccharide-stimulated B cells. The negative autoregulation of IL-10 production is supported by the observation that the inclusion of anti-IL-10 receptor monoclonal antibody enhances IL-10 production and the proliferation of activated B cells. The effects of cytokines on IL-10 production by B10 cells did not correlate with their effects on B-cell proliferation or on IL-10 production by T cells or macrophages. The cytokine-induced changes in IL-10 production occurred on the level of IL-10 gene expression, as confirmed by increased or decreased IL-10 mRNA expression in the presence of a particular cytokine. The regulatory cytokines modulate the number of IL-10-producing cells rather than augmenting or decreasing the secretion of IL-10 on a single-cell level. Altogether these data show that the production of IL-10 by B cells is under the strict regulatory control of cytokines and that individual cytokines differentially regulate the development and activity of regulatory T cells and IL-10-producing regulatory B cells.

• Klíčová slova
• B cells, autoregulation, cytokines, immunosuppression, interleukin-10 production,
• MeSH
• aktivace lymfocytů MeSH
• buněčná diferenciace * účinky léků   MeSH
• cytokiny genetika   metabolismus   MeSH
• homeostáza MeSH
• interferon gama metabolismus   MeSH
• interleukin-10 genetika   metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• lipopolysacharidy farmakologie   MeSH
• messenger RNA metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• proliferace buněk MeSH
• regulace genové exprese MeSH
• regulační B-lymfocyty účinky léků   imunologie   metabolismus   MeSH
• regulační T-lymfocyty imunologie   metabolismus   MeSH
• rekombinantní proteiny metabolismus   MeSH
• signální transdukce MeSH
• TNF-alfa metabolismus   MeSH
• transformující růstový faktor beta1 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• IFNG protein, human MeSH Prohlížeč
• IL10 protein, mouse MeSH Prohlížeč
• interferon gama MeSH
• interleukin-10 MeSH
• lipopolysacharidy MeSH
• messenger RNA MeSH
• rekombinantní proteiny MeSH
• TGFB1 protein, human MeSH Prohlížeč
• TNF-alfa MeSH
• transformující růstový faktor beta1 MeSH

Low-dose human interleukin-2 (hIL-2) treatment is used clinically to treat autoimmune disorders due to the cytokine's preferential expansion of immunosuppressive regulatory T cells (Tregs). However, off-target immune cell activation and short serum half-life limit the clinical potential of IL-2 treatment. Recent work showed that complexes comprising hIL-2 and the anti-hIL-2 antibody F5111 overcome these limitations by preferentially stimulating Tregs over immune effector cells. Although promising, therapeutic translation of this approach is complicated by the need to optimize dosing ratios and by the instability of the cytokine/antibody complex. We leverage structural insights to engineer a single-chain hIL-2/F5111 antibody fusion protein, termed F5111 immunocytokine (IC), which potently and selectively activates and expands Tregs. F5111 IC confers protection in mouse models of colitis and checkpoint inhibitor-induced diabetes mellitus. These results provide a roadmap for IC design and establish a Treg-biased immunotherapy that could be clinically translated for autoimmune disease treatment.

• Klíčová slova
• CP: Immunology, antibody, autoimmune disease, cytokine, immunocytokine, interleukin-2, molecular therapeutics, regulatory T cell,
• MeSH
• autoimunitní nemoci * MeSH
• cytokiny metabolismus   MeSH
• interleukin-2 * MeSH
• lidé MeSH
• myši MeSH
• protilátky metabolismus   MeSH
• regulační T-lymfocyty MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• cytokiny MeSH
• interleukin-2 * MeSH
• protilátky MeSH

Bone marrow-derived mesenchymal stem cells (MSCs) modulate immune response and can produce significant levels of transforming growth factor-β (TGF-β) and interleukin-6 (IL-6). These 2 cytokines represent the key factors that reciprocally regulate the development and polarization of naive T-cells into regulatory T-cell (Treg) population or proinflammatory T helper 17 (Th17) cells. In the present study we demonstrate that MSCs and their products effectively regulate expression of transcription factors Foxp3 and RORγt and control the development of Tregs and Th17 cells in a population of alloantigen-activated mouse spleen cells or purified CD4(+)CD25(-) T-cells. The immunomodulatory effects of MSCs were more pronounced when these cells were stimulated to secrete TGF-β alone or TGF-β together with IL-6. Unstimulated MSCs produce TGF-β, but not IL-6, and the production of TGF-β can be further enhanced by the anti-inflammatory cytokines IL-10 or TGF-β. In the presence of proinflammatory cytokines, MSCs secrete significant levels of IL-6, in addition to a spontaneous production of TGF-β. MSCs producing TGF-β induced preferentially expression of Foxp3 and activation of Tregs, whereas MSC supernatants containing TGF-β together with IL-6 supported RORγt expression and development of Th17 cells. The effects of MSC supernatants were blocked by the inclusion of neutralization monoclonal antibody anti-TGF-β or anti-IL-6 into the culture system. The results showed that MSCs represent important players that reciprocally regulate the development and differentiation of uncommitted naive T-cells into anti-inflammatory Foxp3(+) Tregs or proinflammatory RORγt(+) Th17 cell population and thereby can modulate autoimmune, immunopathological, and transplantation reactions.

• MeSH
• buněčná diferenciace imunologie   MeSH
• buněčné kultury MeSH
• cytokiny biosyntéza   MeSH
• imunita MeSH
• kultivační média speciální farmakologie   MeSH
• mezenchymální kmenové buňky fyziologie   MeSH
• myši MeSH
• parakrinní signalizace imunologie   MeSH
• regulační T-lymfocyty imunologie   MeSH
• T-lymfocyty imunologie   MeSH
• zánět imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• kultivační média speciální MeSH

OBJECTIVE: To describe the role of T-regulatory lymphocytes in pathogenesis of preterm delivery. SETTING: Department of Obstetrics and Gynecology, General University Hospital and 1st Medical Faculty, Charles University, Prague. METHOD: T-regulatory lymphocytes modulate the immune system, secure the tolerance to own antigens and prevent autoimmune disease. During pregnancy is maternal immunity in contact with the semi-allogeneic fetus due to the fetomaternal crosstalk. It seems that maternal immunity and T-regulatory lymphocytes have an effect on premature birth and other pregnancy pathologies. According to the latest data, their role in the immunomodulation of pregnant women seems to be very significant, although we still do not understand many mechanisms.

• Klíčová slova
• T-regulatory cells, premature birth immunomodulation in pregancy.,
• MeSH
• imunomodulace MeSH
• lidé MeSH
• novorozenec MeSH
• plod imunologie   MeSH
• předčasný porod patofyziologie   MeSH
• regulační T-lymfocyty imunologie   metabolismus   MeSH
• těhotenství MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Multiple myeloma (MM) is a plasma cell (PC) disorder and associated with immune impairments. Flow cytometry based phenotyping and quantification of regulatory T cells (Tregs) enable to monitor the immune status of myeloma patients. Apart from enumeration of Tregs, functional characterization using proliferation or suppression assay adds key value in demonstrating the functional value ofTregs. Our study revealed that in MM patientsTregs are elevated compared to healthy subjects, which demonstrate the immune deregulation in MM.

• MeSH
• imunofenotypizace * MeSH
• lidé MeSH
• mnohočetný myelom imunologie   terapie   MeSH
• průtoková cytometrie * MeSH
• regulační T-lymfocyty klasifikace   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Regulatory T-lymphocytes (Treg) are essential for regulation of immune homeostasis and prevention of autoimmune disease development. Regulatory T-cells prevent the onset of autoimmune diseases; they keep immune homeostasis and modulate immune response during infection. Their activity is precisely controlled. Regulatory T-cells belong to one group of immune cells, which can support tumor survival and growth. They realize their function through inhibition of effector T-cells and by regulation of tumor microenvironment through production of various soluble factors. Many publications have proven that the amount of Treg cells is elevated in both solid tumors and in hematologic malignancies. Nevertheless, little is known about mechanisms, which allow increase and maintenance of elevated Treg cells in cancer patients. In this review, we will focus, among others, on the description of function and phenotype of Treg cells, their modulation of humoral immune response and interaction with cancer stem cells. Current development of modern tumor immunotherapy allows new possibilities of influencing Treg cells function.

• MeSH
• imunofenotypizace MeSH
• imunoterapie MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• nádory imunologie   terapie   MeSH
• regulační T-lymfocyty imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH