Heterodimeric β2 integrin surface receptors (CD11a-d/CD18) are specifically expressed by leukocyt... more Heterodimeric β2 integrin surface receptors (CD11a-d/CD18) are specifically expressed by leukocytes that contribute to pathogen uptake, cell migration, immunological synapse formation and cell signaling. In humans, the loss of CD18 expression results in leukocyte adhesion deficiency syndrome (LAD-)1, largely characterized by recurrent severe infections. All available mouse models display the constitutive and ubiquitous knockout of either α or the common β2 (CD18) subunit, which hampers the analysis of the cell type-specific role of β2 integrins in vivo. To overcome this limitation, we generated a CD18 gene floxed mouse strain. Offspring generated from crossing with CD11c-Cre mice displayed the efficient knockdown of β2 integrins, specifically in dendritic cells (DCs). Stimulated β2-integrin-deficient splenic DCs showed enhanced cytokine production and the concomitantly elevated activity of signal transducers and activators of transcription (STAT) 1, 3 and 5, as well as the impaired ...
Allogeneic haematopoietic stem cell transplantation (HSCT) after a reduced‐intensity conditioning... more Allogeneic haematopoietic stem cell transplantation (HSCT) after a reduced‐intensity conditioning (RIC) regimen with fludarabine, melphalan and alemtuzmab is an effective therapy for haematological malignancies. Alemtuzumab, a monoclonal antibody against CD52, a glycosylphosphatidylinositol‐anchor‐bound surface protein on lymphocytes, depletes T cells to prevent graft‐versus‐host disease (GVHD). Despite this, acute and chronic GVHD (a/cGVHD) remain life‐threatening complications after HSCT. The aim of the present study was to identify parameters to predict GVHD. In 69 patients after HSCT, T‐cell subsets were functionally analysed. Reconstitution of CD52neg T cells and CD52neg regulatory T cells (Tregs) correlated with onset, severity and clinical course of aGVHD. Patients with aGVHD showed significantly lower levels of CD52pos T cells compared to patients with cGVHD or without GVHD (P < 0·001). Analysis of T‐cell reconstitution revealed a percentage of <40% of CD52posCD4pos T cells or CD52pos Tregs at day +50 as a risk factor for the development of aGVHD. In contrast, CD52neg Tregs showed significant decreased levels of glycoprotein A repetitions predominant (GARP; P < 0·001), glucocorticoid‐induced TNFR‐related protein (GITR; P < 0·001), chemokine receptor (CXCR3; P = 0·023), C‐C chemokine receptor type 5 (CCR5; P = 0·004), but increased levels of immunoglobulin‐like transcript 3 (ILT3; P = 0·001), as well as a reduced suppressive capacity. We conclude that reconstitution of CD52neg T cells and CD52neg Tregs is a risk factor for development of aGVHD.
Background/Aim: The effects of oxidative stress on various carcinomas were reported in previous s... more Background/Aim: The effects of oxidative stress on various carcinomas were reported in previous studies, but those in intrahepatic cholangiocarcinoma (ICC) have not been fully elucidated. The purpose of this study was, thus, to reveal the effects of oxidative DNA damage and repair enzymes on ICC. Materials and Methods: The levels of 8-hydroxydeoxyguanosine (8-OHdG) and 8-OHdG DNA glycosylase (OGG1) were immunohistochemically evaluated in specimens resected from 63 patients with ICC. Results: Low OGG1 expression was related to tumour depth T4 (p=0.04), venous invasion (p=0.0005), lymphatic vessel invasion (p=0.03), and perineural invasion (p=0.03). Compared to the high-OGG1-expression group, patients with low OGG1 expression had a significantly poorer prognosis (overall survival: p=0.04, recurrence-free survival: p=0.02). Unlike for OGG1, the expression levels of 8-OHdG showed no association with prognosis. Conclusion: Oxidative DNA damage and DNA repair enzymes may be closely related to ICC progression. Cholangiocarcinomas are diverse biliary epithelial tumours involving the intrahepatic perihilar and distal biliary tree (1). Next to hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy, accounting for 10-20% of diagnosed liver cancers, and the overall incidence of ICC has increased progressively worldwide over the last few decades (2-5). The long-term survival of ICC patients is worse than that of HCC patients, which may be related to the high propensity for regional and distant metastases, and lack of effective therapy (6). Risk factors for ICC, such as 3241 This article is freely accessible online.
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 2015
Coevolution of ticks and the vertebrate immune system has led to the development of immunosuppres... more Coevolution of ticks and the vertebrate immune system has led to the development of immunosuppressive molecules that prevent immediate response of skin-resident immune cells to quickly fend off the parasite. In this article, we demonstrate that the tick-derived immunosuppressor sialostatin L restrains IL-9 production by mast cells, whereas degranulation and IL-6 expression are both unaffected. In addition, the expression of IL-1β and IRF4 is strongly reduced in the presence of sialostatin L. Correspondingly, IRF4- or IL-1R-deficient mast cells exhibit a strong impairment in IL-9 production, demonstrating the importance of IRF4 and IL-1 in the regulation of the Il9 locus in mast cells. Furthermore, IRF4 binds to the promoters of Il1b and Il9, suggesting that sialostatin L suppresses mast cell-derived IL-9 preferentially by inhibiting IRF4. In an experimental asthma model, mast cell-specific deficiency in IRF4 or administration of sialostatin L results in a strong reduction in asthma ...
Interferon-regulatory factor 4 (IRF4) is essential for the development of T helper 2 (Th2) and Th... more Interferon-regulatory factor 4 (IRF4) is essential for the development of T helper 2 (Th2) and Th17 cells. Herein, we report that IRF4 is also crucial for the development and function of an interleukin-9 (IL-9)producing CD4 + T cell subset designated Th9. IRF4-deficient CD4 + T cells failed to develop into IL-9-producing Th9 cells, and IRF4-specific siRNA inhibited IL-9 production in wild-type CD4 + T cells. Chromatin-immunoprecipitation (ChIP) analyses revealed direct IRF4 binding to the Il9 promoter in Th9 cells. In a Th9-dependent asthma model, neutralization of IL-9 substantially ameliorated asthma symptoms. The relevance of these findings is emphasized by the fact that the induction of IL-9 production also occurs in human CD4 + T cells accompanied by the upregulation of IRF4. Our data clearly demonstrate the central function of IRF4 in the development of Th9 cells and underline the contribution of this T helper cell subset to the pathogenesis of asthma.
Environmental signals shape host physiology and fitness. Microbiota-derived cues are required to ... more Environmental signals shape host physiology and fitness. Microbiota-derived cues are required to program conventional dendritic cells (cDCs) during the steady state so that they can promptly respond and initiate adaptive immune responses when encountering pathogens. However, the molecular underpinnings of microbiota-guided instructive programs are not well understood. Here, we report that the indigenous microbiota controls constitutive production of type I interferons (IFN-I) by plasmacytoid DCs. Using genome-wide analysis of transcriptional and epigenetic regulomes of cDCs from germ-free and IFN-I receptor (IFNAR)-deficient mice, we found that tonic IFNAR signaling instructs a specific epigenomic and metabolic basal state that poises cDCs for future pathogen combat. However, such beneficial biological function comes with a trade-off. Instructed cDCs can prime T cell responses against harmless peripheral antigens when removing roadblocks of peripheral tolerance. Our data provide fresh insights into the evolutionary trade-offs that come with successful adaptation of vertebrates to their microbial environment.
How disturbances of B cell development provoke adult B acute lymphoblastic leukemia (B-ALL) remai... more How disturbances of B cell development provoke adult B acute lymphoblastic leukemia (B-ALL) remains poorly understood. Here we describe Irf4–/– mice as prone to developing B-ALL with age. Irf4–/– pro/preB cells exhibited impaired differentiative but enhanced proliferative potential in vitro and accumulated in spleens of healthy Irf4–/– mice, suggesting reduced adherence to the IL-7 providing bone marrow niche. Thus selected, pro/preB cells transformed acquiring proliferative IL-7 independency through Jak3 gain-of-function mutations. Targeting JAK signaling with Ruxolitinib in vivo prolonged survival of mice bearing established Irf4–/– leukemia. Intriguingly, organ infiltration including leukemic meningeosis was selectively reduced without affecting blood blast counts. As low IRF4 expression and JAK3 mutations also characterize a subpopulation of Ph-like B-ALL in adult humans, our results imply Irf4–/– mice as a suitable model for investigating preleukemic conditions in adults. Using...
doi:10.1182/blood-2007-01-069229Prepublished online May 14, 2007;2007 110: 1550-1558€€€€Edgar Sch... more doi:10.1182/blood-2007-01-069229Prepublished online May 14, 2007;2007 110: 1550-1558€€€€Edgar Schmitt and Helmut JonuleitPetra Weingarten, Tobias Warger, Jurgen Knop, Stefan Mullner, John Wijdenes, Hansjorg Schild, Jan Kubach, Petra Lutter, Tobias Bopp, Sabine Stoll, Christian Becker, Eva Huter, Christoph Richter,€
CD56+ T cells are a group of pro‐inflammatory CD3+ lymphocytes with characteristics of natural ki... more CD56+ T cells are a group of pro‐inflammatory CD3+ lymphocytes with characteristics of natural killer cells, being involved in antimicrobial immune defense. Here, we performed deep phenotypic profiling of CD3+CD56+ cells in peripheral blood of normal human donors and individuals sensitized to birch‐pollen or/and house dust mite by high‐dimensional mass cytometry combined with manual and computational data analysis. A co‐regulation between major conventional T‐cell subsets and their respective CD3+CD56+ cell counterparts appeared restricted to CD8+, MAIT, and TCRγδ+ T‐cell compartments. Interestingly, we find a co‐regulation of several CD3+CD56+ cell subsets in allergic but not in healthy individuals. Moreover, using FlowSOM, we distinguished a variety of CD56+ T‐cell phenotypes demonstrating a hitherto underestimated heterogeneity among these cells. The novel CD3+CD56+ subset description comprises phenotypes superimposed with naive, memory, type 1, 2, and 17 differentiation stages, in part represented by a phenotypical continuum. Frequencies of two out of 19 CD3+CD56+ FlowSOM clusters were significantly diminished in allergic individuals, demonstrating less frequent presence of cells with cytolytic, presumably protective, capacity in these donors consistent with defective expansion or their recruitment to the affected tissue. Our results contribute to defining specific cell populations to be targeted during therapy for allergic conditions.
The promising development of adoptive immunotherapy over the last four decades has revealed numer... more The promising development of adoptive immunotherapy over the last four decades has revealed numerous therapeutic approaches in which dedicated immune cells are modified and administered to eliminate malignant cells. Starting in the early 1980s, lymphokine activated killer (LAK) cells were the first ex vivo generated NK cell-enriched products utilized for adoptive immunotherapy. Over the past decades, various immunotherapies have been developed, including cytokine-induced killer (CIK) cells, as a peripheral blood mononuclear cells (PBMCs)-based therapeutic product, the adoptive transfer of specific T and NK cell products, and the NK cell line NK-92. In addition to allogeneic NK cells, NK-92 cell products represent a possible “off-the-shelf” therapeutic concept. Recent approaches have successfully enhanced the specificity and cytotoxicity of T, NK, CIK or NK-92 cells towards tumor-specific or associated target antigens generated by genetic engineering of the immune cells, e.g., to exp...
The acidic tumor microenvironment in melanoma drives immune evasion by up-regulating cyclic adeno... more The acidic tumor microenvironment in melanoma drives immune evasion by up-regulating cyclic adenosine monophosphate (cAMP) in tumor-infiltrating monocytes. Here we show that the release of non-toxic concentrations of an adenylate cyclase (AC) inhibitor from poly(sarcosine)-block-poly(L-glutamic acid γ-benzyl ester) (polypept(o)id) copolymer micelles restores antitumor immunity. In combination with selective, non-therapeutic regulatory T cell depletion, AC inhibitor micelles achieve a complete remission of established B16-F10-OVA tumors. Single-cell sequencing of melanoma-infiltrating immune cells shows that AC inhibitor micelles reduce the number of anti-inflammatory myeloid cells and checkpoint receptor expression on T cells. AC inhibitor micelles thus represent an immunotherapeutic measure to counteract melanoma immune escape.
CONFLIC T OF INTERE S T Paweł Gajdanowicz, Dries Van Elst, Andrzej Eljaszewicz and Sylwia Smolińs... more CONFLIC T OF INTERE S T Paweł Gajdanowicz, Dries Van Elst, Andrzej Eljaszewicz and Sylwia Smolińska have no conflict of interest to declare. Liam O'Mahony reports personal fees from Alimentary Health Ltd, grants from GSK, outside the submitted work. Alexander Kettner, reports personal fees from Anergis SA, during the conduct of the study. Marek Jutel, reports personal fees from ALK-Abello, personal fees from Allergopharma, personal fees from Stallergenes, personal fees from Anergis, personal fees from Allergy Therapeutics, personal fees from Circassia, personal fees from Leti, personal fees from Biomay, personal fees from HAL, during the conduct of the study; personal fees from Astra-Zeneca, personal fees from GSK, personal fees from Novartis, personal fees from Teva, personal fees from Vectura, personal fees from UCB, personal fees from Takeda, personal fees from Roche, personal fees from Janssen, personal fees from Medimmune, personal fees from Chiesi, outside the submitted work.
IL-9 has lent its numerical designation to the Th9 subset of CD4+ Th cells, although it is also p... more IL-9 has lent its numerical designation to the Th9 subset of CD4+ Th cells, although it is also produced by additional cell types, including mast cells. It is a pleiotropic cytokine involved in allergic reactions, parasitic infections, autoimmune inflammation, and cancer immunity. In this article, we provide evidence that NFATc2 has contradictory functions in the expression of IL-9 in murine Th9 cells and bone marrow-derived mast cells (BMMC). The basis for this is our observation that the production of IL-9 in NFATc2-deficient Th9 cells is increased, whereas it is decreased in BMMC devoid of NFATc2. In addition, NFATc2 deficiency almost completely abrogates the expression of IL-3 in both cell types. However, selectively in BMMC, the production of IL-9 critically depends on autocrine IL-3 acting via the sustained activation of STAT5 on the expression of IL-9. Furthermore, we demonstrate that IL-3 acts independently and synergistically with IL-1β on the production of IL-9. Taken together, we highlight NFATc2-driven production of autocrine IL-3 as a critical and cell type-specific component for IL-9 expression in BMMC.
Interleukin-17A– (IL-17A) and IL-17F–producing CD4+ T helper cells (TH17 cells) are implicated in... more Interleukin-17A– (IL-17A) and IL-17F–producing CD4+ T helper cells (TH17 cells) are implicated in the development of chronic inflammatory diseases, such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). TH17 cells also orchestrate leukocyte invasion of the central nervous system (CNS) and subsequent tissue damage. However, the role of IL-17A and IL-17F as effector cytokines is still confused with the encephalitogenic function of the cells that produce these cytokines, namely, TH17 cells, fueling a long-standing debate in the neuroimmunology field. Here, we demonstrated that mice deficient for IL-17A/F lose their susceptibility to EAE, which correlated with an altered composition of their gut microbiota. However, loss of IL-17A/F in TH cells did not diminish their encephalitogenic capacity. Reconstitution of a wild-type–like intestinal microbiota or reintroduction of IL-17A specifically into the gut epithelium of IL-17A/F–deficient mice rees...
The transcription factor Nrf2 regulates oxidative stress responses. However, the specific functio... more The transcription factor Nrf2 regulates oxidative stress responses. However, the specific function of Nrf2 in Tregs, the central regulators of immune homeostasis, is unclear. Here, we report an unexpected but important role of Nrf2 in Tregs. Nrf2 expression driven by Foxp3 specific deletion of Keap1 resulted in an autoinflammatory phenotype with enhanced effector T cell activation and immune cell infiltrates in the lung. While early postnatal death of mice with Foxp3 specific deletion of Keap1 was most probably due to ectopic Foxp3 cre expression and subsequent Keap1 deletion in epithelial cells, bone marrow chimeras suggest that Nrf2 activation intrinsically in Tregs contributes to a loss of Treg cells and diminished peripheral tolerance. Moreover, Nrf2 activation was associated with a loss of Foxp3 expression, but an enhanced glucose uptake and mTOR activity in Tregs, thus mimicking a metabolic phenotype that is associated with impaired lineage stability and cell functioning.
Highlights d Glycolytic index in melanoma negatively correlates with response to anti-PD1 therapy... more Highlights d Glycolytic index in melanoma negatively correlates with response to anti-PD1 therapy d Blocking lactate transport or knock out of glycolytic genes improves checkpoint therapy d Diclofenac blocks the lactate transporters MCT1 and MCT4 in a COX-independent manner d Inhibition of glycolysis by MCT blockade does not impede T cell function
The massive infiltration of lymphocytes into the skin is a hallmark of numerous human skin disord... more The massive infiltration of lymphocytes into the skin is a hallmark of numerous human skin disorders. By co-culturing murine keratinocytes with splenic T cells we demonstrate here that T cells affect and control the synthesis and secretion of chemokines by keratinocytes. While pre-activated CD8 + T cells induce the synthesis of CXCL9 and CXCL10 in keratinocytes and keep in check the synthesis of CXCL1, CXCL5, and CCL20, keratinocytes dampen the synthesis of CCL3 and CCL4 in pre-activated CD8 + T cells. One key molecule is IFN-γ that is synthesized by CD8 + T cells under the control of NFATc1 and NFATc2. CD8 + T cells deficient for both NFAT factors are unable to induce CXCL9 and CXCL10 expression. In addition, CD8 + T cells induced numerous type I IFN-inducible "defense genes" in keratinocytes encoding the PD1 and CD40 ligands, TNF-α and caspase-1. The enhanced expression of type I IFN-inducible genes resembles the gene expression pattern at the dermal/epidermal interface in lichen planus, an inflammatory T lymphocyte-driven skin disease, in which we detected the expression of CXCL10 in keratinocytes in close vicinity to the infiltration front of T cells. These data reflect the multifaceted interplay of lymphocytes with keratinocytes at the molecular level.
Heterodimeric β2 integrin surface receptors (CD11a-d/CD18) are specifically expressed by leukocyt... more Heterodimeric β2 integrin surface receptors (CD11a-d/CD18) are specifically expressed by leukocytes that contribute to pathogen uptake, cell migration, immunological synapse formation and cell signaling. In humans, the loss of CD18 expression results in leukocyte adhesion deficiency syndrome (LAD-)1, largely characterized by recurrent severe infections. All available mouse models display the constitutive and ubiquitous knockout of either α or the common β2 (CD18) subunit, which hampers the analysis of the cell type-specific role of β2 integrins in vivo. To overcome this limitation, we generated a CD18 gene floxed mouse strain. Offspring generated from crossing with CD11c-Cre mice displayed the efficient knockdown of β2 integrins, specifically in dendritic cells (DCs). Stimulated β2-integrin-deficient splenic DCs showed enhanced cytokine production and the concomitantly elevated activity of signal transducers and activators of transcription (STAT) 1, 3 and 5, as well as the impaired ...
Allogeneic haematopoietic stem cell transplantation (HSCT) after a reduced‐intensity conditioning... more Allogeneic haematopoietic stem cell transplantation (HSCT) after a reduced‐intensity conditioning (RIC) regimen with fludarabine, melphalan and alemtuzmab is an effective therapy for haematological malignancies. Alemtuzumab, a monoclonal antibody against CD52, a glycosylphosphatidylinositol‐anchor‐bound surface protein on lymphocytes, depletes T cells to prevent graft‐versus‐host disease (GVHD). Despite this, acute and chronic GVHD (a/cGVHD) remain life‐threatening complications after HSCT. The aim of the present study was to identify parameters to predict GVHD. In 69 patients after HSCT, T‐cell subsets were functionally analysed. Reconstitution of CD52neg T cells and CD52neg regulatory T cells (Tregs) correlated with onset, severity and clinical course of aGVHD. Patients with aGVHD showed significantly lower levels of CD52pos T cells compared to patients with cGVHD or without GVHD (P < 0·001). Analysis of T‐cell reconstitution revealed a percentage of <40% of CD52posCD4pos T cells or CD52pos Tregs at day +50 as a risk factor for the development of aGVHD. In contrast, CD52neg Tregs showed significant decreased levels of glycoprotein A repetitions predominant (GARP; P < 0·001), glucocorticoid‐induced TNFR‐related protein (GITR; P < 0·001), chemokine receptor (CXCR3; P = 0·023), C‐C chemokine receptor type 5 (CCR5; P = 0·004), but increased levels of immunoglobulin‐like transcript 3 (ILT3; P = 0·001), as well as a reduced suppressive capacity. We conclude that reconstitution of CD52neg T cells and CD52neg Tregs is a risk factor for development of aGVHD.
Background/Aim: The effects of oxidative stress on various carcinomas were reported in previous s... more Background/Aim: The effects of oxidative stress on various carcinomas were reported in previous studies, but those in intrahepatic cholangiocarcinoma (ICC) have not been fully elucidated. The purpose of this study was, thus, to reveal the effects of oxidative DNA damage and repair enzymes on ICC. Materials and Methods: The levels of 8-hydroxydeoxyguanosine (8-OHdG) and 8-OHdG DNA glycosylase (OGG1) were immunohistochemically evaluated in specimens resected from 63 patients with ICC. Results: Low OGG1 expression was related to tumour depth T4 (p=0.04), venous invasion (p=0.0005), lymphatic vessel invasion (p=0.03), and perineural invasion (p=0.03). Compared to the high-OGG1-expression group, patients with low OGG1 expression had a significantly poorer prognosis (overall survival: p=0.04, recurrence-free survival: p=0.02). Unlike for OGG1, the expression levels of 8-OHdG showed no association with prognosis. Conclusion: Oxidative DNA damage and DNA repair enzymes may be closely related to ICC progression. Cholangiocarcinomas are diverse biliary epithelial tumours involving the intrahepatic perihilar and distal biliary tree (1). Next to hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy, accounting for 10-20% of diagnosed liver cancers, and the overall incidence of ICC has increased progressively worldwide over the last few decades (2-5). The long-term survival of ICC patients is worse than that of HCC patients, which may be related to the high propensity for regional and distant metastases, and lack of effective therapy (6). Risk factors for ICC, such as 3241 This article is freely accessible online.
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 2015
Coevolution of ticks and the vertebrate immune system has led to the development of immunosuppres... more Coevolution of ticks and the vertebrate immune system has led to the development of immunosuppressive molecules that prevent immediate response of skin-resident immune cells to quickly fend off the parasite. In this article, we demonstrate that the tick-derived immunosuppressor sialostatin L restrains IL-9 production by mast cells, whereas degranulation and IL-6 expression are both unaffected. In addition, the expression of IL-1β and IRF4 is strongly reduced in the presence of sialostatin L. Correspondingly, IRF4- or IL-1R-deficient mast cells exhibit a strong impairment in IL-9 production, demonstrating the importance of IRF4 and IL-1 in the regulation of the Il9 locus in mast cells. Furthermore, IRF4 binds to the promoters of Il1b and Il9, suggesting that sialostatin L suppresses mast cell-derived IL-9 preferentially by inhibiting IRF4. In an experimental asthma model, mast cell-specific deficiency in IRF4 or administration of sialostatin L results in a strong reduction in asthma ...
Interferon-regulatory factor 4 (IRF4) is essential for the development of T helper 2 (Th2) and Th... more Interferon-regulatory factor 4 (IRF4) is essential for the development of T helper 2 (Th2) and Th17 cells. Herein, we report that IRF4 is also crucial for the development and function of an interleukin-9 (IL-9)producing CD4 + T cell subset designated Th9. IRF4-deficient CD4 + T cells failed to develop into IL-9-producing Th9 cells, and IRF4-specific siRNA inhibited IL-9 production in wild-type CD4 + T cells. Chromatin-immunoprecipitation (ChIP) analyses revealed direct IRF4 binding to the Il9 promoter in Th9 cells. In a Th9-dependent asthma model, neutralization of IL-9 substantially ameliorated asthma symptoms. The relevance of these findings is emphasized by the fact that the induction of IL-9 production also occurs in human CD4 + T cells accompanied by the upregulation of IRF4. Our data clearly demonstrate the central function of IRF4 in the development of Th9 cells and underline the contribution of this T helper cell subset to the pathogenesis of asthma.
Environmental signals shape host physiology and fitness. Microbiota-derived cues are required to ... more Environmental signals shape host physiology and fitness. Microbiota-derived cues are required to program conventional dendritic cells (cDCs) during the steady state so that they can promptly respond and initiate adaptive immune responses when encountering pathogens. However, the molecular underpinnings of microbiota-guided instructive programs are not well understood. Here, we report that the indigenous microbiota controls constitutive production of type I interferons (IFN-I) by plasmacytoid DCs. Using genome-wide analysis of transcriptional and epigenetic regulomes of cDCs from germ-free and IFN-I receptor (IFNAR)-deficient mice, we found that tonic IFNAR signaling instructs a specific epigenomic and metabolic basal state that poises cDCs for future pathogen combat. However, such beneficial biological function comes with a trade-off. Instructed cDCs can prime T cell responses against harmless peripheral antigens when removing roadblocks of peripheral tolerance. Our data provide fresh insights into the evolutionary trade-offs that come with successful adaptation of vertebrates to their microbial environment.
How disturbances of B cell development provoke adult B acute lymphoblastic leukemia (B-ALL) remai... more How disturbances of B cell development provoke adult B acute lymphoblastic leukemia (B-ALL) remains poorly understood. Here we describe Irf4–/– mice as prone to developing B-ALL with age. Irf4–/– pro/preB cells exhibited impaired differentiative but enhanced proliferative potential in vitro and accumulated in spleens of healthy Irf4–/– mice, suggesting reduced adherence to the IL-7 providing bone marrow niche. Thus selected, pro/preB cells transformed acquiring proliferative IL-7 independency through Jak3 gain-of-function mutations. Targeting JAK signaling with Ruxolitinib in vivo prolonged survival of mice bearing established Irf4–/– leukemia. Intriguingly, organ infiltration including leukemic meningeosis was selectively reduced without affecting blood blast counts. As low IRF4 expression and JAK3 mutations also characterize a subpopulation of Ph-like B-ALL in adult humans, our results imply Irf4–/– mice as a suitable model for investigating preleukemic conditions in adults. Using...
doi:10.1182/blood-2007-01-069229Prepublished online May 14, 2007;2007 110: 1550-1558€€€€Edgar Sch... more doi:10.1182/blood-2007-01-069229Prepublished online May 14, 2007;2007 110: 1550-1558€€€€Edgar Schmitt and Helmut JonuleitPetra Weingarten, Tobias Warger, Jurgen Knop, Stefan Mullner, John Wijdenes, Hansjorg Schild, Jan Kubach, Petra Lutter, Tobias Bopp, Sabine Stoll, Christian Becker, Eva Huter, Christoph Richter,€
CD56+ T cells are a group of pro‐inflammatory CD3+ lymphocytes with characteristics of natural ki... more CD56+ T cells are a group of pro‐inflammatory CD3+ lymphocytes with characteristics of natural killer cells, being involved in antimicrobial immune defense. Here, we performed deep phenotypic profiling of CD3+CD56+ cells in peripheral blood of normal human donors and individuals sensitized to birch‐pollen or/and house dust mite by high‐dimensional mass cytometry combined with manual and computational data analysis. A co‐regulation between major conventional T‐cell subsets and their respective CD3+CD56+ cell counterparts appeared restricted to CD8+, MAIT, and TCRγδ+ T‐cell compartments. Interestingly, we find a co‐regulation of several CD3+CD56+ cell subsets in allergic but not in healthy individuals. Moreover, using FlowSOM, we distinguished a variety of CD56+ T‐cell phenotypes demonstrating a hitherto underestimated heterogeneity among these cells. The novel CD3+CD56+ subset description comprises phenotypes superimposed with naive, memory, type 1, 2, and 17 differentiation stages, in part represented by a phenotypical continuum. Frequencies of two out of 19 CD3+CD56+ FlowSOM clusters were significantly diminished in allergic individuals, demonstrating less frequent presence of cells with cytolytic, presumably protective, capacity in these donors consistent with defective expansion or their recruitment to the affected tissue. Our results contribute to defining specific cell populations to be targeted during therapy for allergic conditions.
The promising development of adoptive immunotherapy over the last four decades has revealed numer... more The promising development of adoptive immunotherapy over the last four decades has revealed numerous therapeutic approaches in which dedicated immune cells are modified and administered to eliminate malignant cells. Starting in the early 1980s, lymphokine activated killer (LAK) cells were the first ex vivo generated NK cell-enriched products utilized for adoptive immunotherapy. Over the past decades, various immunotherapies have been developed, including cytokine-induced killer (CIK) cells, as a peripheral blood mononuclear cells (PBMCs)-based therapeutic product, the adoptive transfer of specific T and NK cell products, and the NK cell line NK-92. In addition to allogeneic NK cells, NK-92 cell products represent a possible “off-the-shelf” therapeutic concept. Recent approaches have successfully enhanced the specificity and cytotoxicity of T, NK, CIK or NK-92 cells towards tumor-specific or associated target antigens generated by genetic engineering of the immune cells, e.g., to exp...
The acidic tumor microenvironment in melanoma drives immune evasion by up-regulating cyclic adeno... more The acidic tumor microenvironment in melanoma drives immune evasion by up-regulating cyclic adenosine monophosphate (cAMP) in tumor-infiltrating monocytes. Here we show that the release of non-toxic concentrations of an adenylate cyclase (AC) inhibitor from poly(sarcosine)-block-poly(L-glutamic acid γ-benzyl ester) (polypept(o)id) copolymer micelles restores antitumor immunity. In combination with selective, non-therapeutic regulatory T cell depletion, AC inhibitor micelles achieve a complete remission of established B16-F10-OVA tumors. Single-cell sequencing of melanoma-infiltrating immune cells shows that AC inhibitor micelles reduce the number of anti-inflammatory myeloid cells and checkpoint receptor expression on T cells. AC inhibitor micelles thus represent an immunotherapeutic measure to counteract melanoma immune escape.
CONFLIC T OF INTERE S T Paweł Gajdanowicz, Dries Van Elst, Andrzej Eljaszewicz and Sylwia Smolińs... more CONFLIC T OF INTERE S T Paweł Gajdanowicz, Dries Van Elst, Andrzej Eljaszewicz and Sylwia Smolińska have no conflict of interest to declare. Liam O'Mahony reports personal fees from Alimentary Health Ltd, grants from GSK, outside the submitted work. Alexander Kettner, reports personal fees from Anergis SA, during the conduct of the study. Marek Jutel, reports personal fees from ALK-Abello, personal fees from Allergopharma, personal fees from Stallergenes, personal fees from Anergis, personal fees from Allergy Therapeutics, personal fees from Circassia, personal fees from Leti, personal fees from Biomay, personal fees from HAL, during the conduct of the study; personal fees from Astra-Zeneca, personal fees from GSK, personal fees from Novartis, personal fees from Teva, personal fees from Vectura, personal fees from UCB, personal fees from Takeda, personal fees from Roche, personal fees from Janssen, personal fees from Medimmune, personal fees from Chiesi, outside the submitted work.
IL-9 has lent its numerical designation to the Th9 subset of CD4+ Th cells, although it is also p... more IL-9 has lent its numerical designation to the Th9 subset of CD4+ Th cells, although it is also produced by additional cell types, including mast cells. It is a pleiotropic cytokine involved in allergic reactions, parasitic infections, autoimmune inflammation, and cancer immunity. In this article, we provide evidence that NFATc2 has contradictory functions in the expression of IL-9 in murine Th9 cells and bone marrow-derived mast cells (BMMC). The basis for this is our observation that the production of IL-9 in NFATc2-deficient Th9 cells is increased, whereas it is decreased in BMMC devoid of NFATc2. In addition, NFATc2 deficiency almost completely abrogates the expression of IL-3 in both cell types. However, selectively in BMMC, the production of IL-9 critically depends on autocrine IL-3 acting via the sustained activation of STAT5 on the expression of IL-9. Furthermore, we demonstrate that IL-3 acts independently and synergistically with IL-1β on the production of IL-9. Taken together, we highlight NFATc2-driven production of autocrine IL-3 as a critical and cell type-specific component for IL-9 expression in BMMC.
Interleukin-17A– (IL-17A) and IL-17F–producing CD4+ T helper cells (TH17 cells) are implicated in... more Interleukin-17A– (IL-17A) and IL-17F–producing CD4+ T helper cells (TH17 cells) are implicated in the development of chronic inflammatory diseases, such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). TH17 cells also orchestrate leukocyte invasion of the central nervous system (CNS) and subsequent tissue damage. However, the role of IL-17A and IL-17F as effector cytokines is still confused with the encephalitogenic function of the cells that produce these cytokines, namely, TH17 cells, fueling a long-standing debate in the neuroimmunology field. Here, we demonstrated that mice deficient for IL-17A/F lose their susceptibility to EAE, which correlated with an altered composition of their gut microbiota. However, loss of IL-17A/F in TH cells did not diminish their encephalitogenic capacity. Reconstitution of a wild-type–like intestinal microbiota or reintroduction of IL-17A specifically into the gut epithelium of IL-17A/F–deficient mice rees...
The transcription factor Nrf2 regulates oxidative stress responses. However, the specific functio... more The transcription factor Nrf2 regulates oxidative stress responses. However, the specific function of Nrf2 in Tregs, the central regulators of immune homeostasis, is unclear. Here, we report an unexpected but important role of Nrf2 in Tregs. Nrf2 expression driven by Foxp3 specific deletion of Keap1 resulted in an autoinflammatory phenotype with enhanced effector T cell activation and immune cell infiltrates in the lung. While early postnatal death of mice with Foxp3 specific deletion of Keap1 was most probably due to ectopic Foxp3 cre expression and subsequent Keap1 deletion in epithelial cells, bone marrow chimeras suggest that Nrf2 activation intrinsically in Tregs contributes to a loss of Treg cells and diminished peripheral tolerance. Moreover, Nrf2 activation was associated with a loss of Foxp3 expression, but an enhanced glucose uptake and mTOR activity in Tregs, thus mimicking a metabolic phenotype that is associated with impaired lineage stability and cell functioning.
Highlights d Glycolytic index in melanoma negatively correlates with response to anti-PD1 therapy... more Highlights d Glycolytic index in melanoma negatively correlates with response to anti-PD1 therapy d Blocking lactate transport or knock out of glycolytic genes improves checkpoint therapy d Diclofenac blocks the lactate transporters MCT1 and MCT4 in a COX-independent manner d Inhibition of glycolysis by MCT blockade does not impede T cell function
The massive infiltration of lymphocytes into the skin is a hallmark of numerous human skin disord... more The massive infiltration of lymphocytes into the skin is a hallmark of numerous human skin disorders. By co-culturing murine keratinocytes with splenic T cells we demonstrate here that T cells affect and control the synthesis and secretion of chemokines by keratinocytes. While pre-activated CD8 + T cells induce the synthesis of CXCL9 and CXCL10 in keratinocytes and keep in check the synthesis of CXCL1, CXCL5, and CCL20, keratinocytes dampen the synthesis of CCL3 and CCL4 in pre-activated CD8 + T cells. One key molecule is IFN-γ that is synthesized by CD8 + T cells under the control of NFATc1 and NFATc2. CD8 + T cells deficient for both NFAT factors are unable to induce CXCL9 and CXCL10 expression. In addition, CD8 + T cells induced numerous type I IFN-inducible "defense genes" in keratinocytes encoding the PD1 and CD40 ligands, TNF-α and caspase-1. The enhanced expression of type I IFN-inducible genes resembles the gene expression pattern at the dermal/epidermal interface in lichen planus, an inflammatory T lymphocyte-driven skin disease, in which we detected the expression of CXCL10 in keratinocytes in close vicinity to the infiltration front of T cells. These data reflect the multifaceted interplay of lymphocytes with keratinocytes at the molecular level.
Uploads
Papers by Tobias Bopp