Publications
52 results found
Subramanian K, Paul S, Libby A, et al., 2023, HERV1-env Induces Unfolded Protein Response Activation in Autoimmune Liver Disease: A Potential Mechanism for Regulatory T Cell Dysfunction., J Immunol, Vol: 210, Pages: 732-744
Regulatory T cells (Tregs) are not terminally differentiated but can acquire effector properties. Here we report an increased expression of human endogenous retrovirus 1 (HERV1-env) proteins in Tregs of patients with de novo autoimmune hepatitis and autoimmune hepatitis, which induces endoplasmic reticulum (ER) stress. HERV1-env-triggered ER stress activates all three branches (IRE1, ATF6, and PERK) of the unfolded protein response (UPR). Our coimmunoprecipitation studies show an interaction between HERV1-env proteins and the ATF6 branch of the UPR. The activated form of ATF6α activates the expression of RORC and STAT3 by binding to promoter sequences and induces IL-17A production. Silencing of HERV1-env results in recovery of Treg suppressive function. These findings identify ER stress and UPR activation as key factors driving Treg plasticity (species: human).
Burnham KL, Maher AK, Jones EM, et al., 2022, Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19, Nature Communications, Vol: 13, Pages: 1-17, ISSN: 2041-1723
Although alterations in myeloid cells have been observed in COVID-19, the specific underlying mechanisms are not completely understood. Here, we examine the function of classical CD14+ monocytes in patients with mild and moderate COVID-19 during the acute phase of infection and in healthy individuals. Monocytes from COVID-19 patients display altered expression of cell surface receptors and a dysfunctional metabolic profile that distinguish them from healthy monocytes. Secondary pathogen sensing ex vivo leads to defects in pro-inflammatory cytokine and type-I IFN production in moderate COVID-19 cases, together with defects in glycolysis. COVID-19 monocytes switch their gene expression profile from canonical innate immune to pro-thrombotic signatures and are functionally pro-thrombotic, both at baseline and following ex vivo stimulation with SARS-CoV-2. Transcriptionally, COVID-19 monocytes are characterized by enrichment of pathways involved in hemostasis, immunothrombosis, platelet aggregation and other accessory pathways to platelet activation and clot formation. These results identify a potential mechanism by which monocyte dysfunction may contribute to COVID-19 pathology.
Saputil RC, Dunster JL, Kriek N, et al., 2022, Characterisation of Platelet Sensitivity in Severe COVID-19, Publisher: AMER SOC HEMATOLOGY, Pages: 11263-11264, ISSN: 0006-4971
Sourij C, Aziz F, Kojzar H, et al., 2022, SARS-CoV-2S antibody formation is not impaired in people with type 1 or type 2 diabetes, but the antibody level falls more rapidly in this collective - the -COVAC-DM study, Publisher: SPRINGER WIEN, Pages: 259-260, ISSN: 0043-5325
Malik A, Toth EN, Teng MS, et al., 2022, Distorted TCR repertoires define multisystem inflammatory syndrome in children, PLOS ONE, Vol: 17, ISSN: 1932-6203
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- Citations: 1
Sourij C, Aziz F, Kojzar H, et al., 2022, Severe acute respiratory syndrome coronavirus 2 spike antibody level decline is more pronounced after the second vaccination, but response to the third vaccination is similar in people with type 1 and type 2 diabetes compared with healthy controls: The prospective COVAC-DM cohort study, DIABETES OBESITY & METABOLISM, ISSN: 1462-8902
Dominguez-Villar M, 2022, TKT deficiency puts T-regs to rest, NATURE METABOLISM, Vol: 4, Pages: 503-504
Pompura SL, Hafler DA, Dominguez-Villar M, 2022, Fatty acid metabolism and T cells in multiple sclerosis., Frontiers in Immunology, Vol: 13, Pages: 1-15, ISSN: 1664-3224
Cellular metabolic remodeling is intrinsically linked to the development, activation, differentiation, function, and survival of T cells. T cells transition from a catabolic, naïve state to an anabolic effector state upon T cell activation. Subsequently, specialization of T cells into T helper (Th) subsets, including regulatory T cells (Treg), requires fine-tuning of metabolic programs that better support and optimize T cell functions for that particular environment. Increasingly, studies have shown that changes in nutrient availability at both the cellular and organismal level during disease states can alter T cell function, highlighting the importance of better characterizing metabolic-immune axes in both physiological and disease settings. In support of these data, a growing body of evidence is emerging that shows specific lipid species are capable of altering the inflammatory functional phenotypes of T cells. In this review we summarize the metabolic programs shown to support naïve and effector T cells, and those driving Th subsets. We then discuss changes to lipid profiles in patients with multiple sclerosis, and focus on how the presence of specific lipid species can alter cellular metabolism and function of T cells.
Cameron B, Zaheer SA, Dominguez-Villar M, 2022, Control of CD4(+) T Cell Differentiation and Function by PI3K Isoforms, PI3K AND AKT ISOFORMS IN IMMUNITY, Vol: 436, Pages: 197-216, ISSN: 0070-217X
Selck C, Dominguez-Villar M, 2021, Antigen-specific regulatory t cell therapy in autoimmune diseases and transplantation, Frontiers in Immunology, Vol: 12, ISSN: 1664-3224
Regulatory T (Treg) cells are a heterogenous population of immunosuppressive T cells whose therapeutic potential for the treatment of autoimmune diseases and graft rejection is currently being explored. While clinical trial results thus far support the safety and efficacy of adoptive therapies using polyclonal Treg cells, some studies suggest that antigen-specific Treg cells are more potent in regulating and improving immune tolerance in a disease-specific manner. Hence, several approaches to generate and/or expand antigen-specific Treg cells in vitro or in vivo are currently under investigation. However, antigen-specific Treg cell therapies face additional challenges that require further consideration, including the identification of disease-relevant antigens as well as the in vivo stability and migratory behavior of Treg cells following transfer. In this review, we discuss these approaches and the potential limitations and describe prospective strategies to enhance the efficacy of antigen-specific Treg cell treatments in autoimmunity and transplantation.
Piconese S, Walker LSK, Dominguez-Villar M, 2021, Editorial: Control of regulatory T cell stability, plasticity, and function in Health and disease, Frontiers in Immunology, Vol: 11, ISSN: 1664-3224
Pompura SL, Wagner A, Kitz A, et al., 2021, Oleic acid restores suppressive defects in tissue-resident FOXP3 Tregs from patients with multiple sclerosis, JOURNAL OF CLINICAL INVESTIGATION, Vol: 131, ISSN: 0021-9738
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- Citations: 30
Lucca LE, Dominguez-Villar M, 2020, Modulation of regulatory T cell function and stability by co-inhibitory receptors, NATURE REVIEWS IMMUNOLOGY, Vol: 20, Pages: 680-693, ISSN: 1474-1733
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- Citations: 76
de Marcken M, Dhaliwal K, Danielsen AC, et al., 2019, TLR7 and TLR8 activate distinct pathways in monocytes during RNA virus infection, Science Signaling, Vol: 12, Pages: 1-18, ISSN: 1945-0877
Human blood CD14+ monocytes are bone marrow–derived white blood cells that sense and respond to pathogens. Although innate immune activation by RNA viruses preferentially occurs through intracellular RIG-I–like receptors, other nucleic acid recognition receptors, such as Toll-like receptors (TLRs), play a role in finely programming the final outcome of virus infection. Here, we dissected how human monocytes respond to infection with either Coxsackie (CV), encephalomyocarditis (EMCV), influenza A (IAV), measles (MV), Sendai (SV), or vesicular stomatitis (VSV) virus. We found that in monocytes, type I interferon (IFN) and cytokine responses to infection were RNA virus specific and differentially involved TLR7 and TLR8, which sense single-stranded RNA. These TLRs activated distinct signaling cascades in monocytes, which correlated with differences in the production of cytokines involved in the polarization of CD4+ T helper cells. Furthermore, we found that TLR7 signaling specifically increased expression of the transcription factor FOSL1, which reduced IL-27 and TNFα production by monocytes. TLR7, but not TLR8, activation of monocytes also stimulated Ca2+ flux that prevented type I IFN responses. Our work demonstrates that in human monocytes, TLR7 and TLR8 triggered different signaling pathways that contribute to distinct phenotypes during RNA virus infection. In addition, we defined individual targets within these pathways that promoted specific T helper and antiviral responses.
Kitz A, de Marcken M, Gautron A-S, et al., 2019, AKT isoforms modulate Th1-like Treg generation and function in human autoimmune disease (vol 17, pg 1169, 2018), EMBO REPORTS, Vol: 20, ISSN: 1469-221X
Dominguez-Villar M, Raddassi K, Danielsen AC, et al., 2019, Fingolimod modulates T cell phenotype and regulatory T cell plasticity in vivo (vol 96, pg 40, 2019), JOURNAL OF AUTOIMMUNITY, Vol: 102, Pages: 179-179, ISSN: 0896-8411
Sumida T, Lincoln MR, Ukeje CM, et al., 2019, Activated beta-catenin in Foxp3(+) regulatory T cells links inflammatory environments to autoimmunity (vol 19, pg 1391, 2018), NATURE IMMUNOLOGY, Vol: 20, Pages: 943-943, ISSN: 1529-2908
Lucca LE, Axisa P-P, Singer ER, et al., 2019, TIGIT signaling restores suppressor function of Th1 Tregs, JCI insight, Vol: 4, ISSN: 2379-3708
Th1 Tregs are characterized by the acquisition of proinflammatory cytokine secretion and reduced suppressor activity. Th1 Tregs are found at increased frequency in autoimmune diseases, including type 1 diabetes and multiple sclerosis (MS). We have previously reported that in vitro stimulation with IL-12 recapitulates the functional and molecular features of MS-associated Th1 Tregs, revealing a central role for hyperactivation of the Akt pathway in their induction. TIGIT is a newly identified coinhibitory receptor that marks Tregs that specifically control Th1 and Th17 responses. Here, we report that signaling through TIGIT counteracts the action of IL-12 in inducing the Th1 program. Specifically, TIGIT signaling represses production of IFN-γ and T-bet expression and restores suppressor function in Tregs treated with IL-12. FoxO1 functional inhibition abolishes the protective effect of TIGIT, indicating that TIGIT signaling promotes FoxO1 nuclear localization. Consistent with this observation, signaling through TIGIT leads to a rapid suppression of Akt function and FoxO1 phosphorylation. Finally, TIGIT stimulation reduces the production of IFN-γ and corrects the suppressor defect of Tregs from patients with MS. Our results indicate an important role for TIGIT in controlling the functional stability of Tregs through repression of Akt, suggesting that the TIGIT pathway could be targeted for immunomodulatory therapies in human autoimmune disorders.
Dominguez-Villar M, Raddassi K, Danielsen AC, et al., 2019, Fingolimod modulates T cell phenotype and regulatory T cell plasticity in vivo, Journal of Autoimmunity, Vol: 96, Pages: 40-49, ISSN: 0896-8411
Fingolimod is an approved therapeutic option for patients with relapsing-remitting multiple sclerosis that primarily functions by sequestering T cells in lymph nodes inhibiting their egress to the central nervous system. However, recent data suggests that Fingolimod may also directly affect the immune cell function. Here we examined the in vivo effects of Fingolimod in modulating the phenotype and function of T cell and Foxp3 regulatory T cell populations in patients with multiple sclerosis under Fingolimod treatment. Besides decreasing the cell numbers in peripheral blood and sera levels of pro-inflammatory cytokines, Fingolimod inhibited the expression of Th1 and Th17 cytokines on CD4+ T cells and increased the expression of exhaustion markers. Furthermore, treatment increased the frequency of regulatory T cells in blood and inhibited the Th1-like phenotype that is characteristic of patients with multiple sclerosis, augmenting the expression of markers associated with increased suppressive function. Overall, our data suggest that Fingolimod performs other important immunomodulatory functions besides altering T cell migratory capacities, with consequences for other autoimmune pathologies characterized by excessive Th1/Th17 responses and Th1-like regulatory T cell effector phenotypes.
Sumida T, Lincoln MR, Ukeje CM, et al., 2018, Activated β-catenin in Foxp3+ regulatory T cells links inflammatory environments to autoimmunity., Nature Immunology, Vol: 19, Pages: 1391-1402, ISSN: 1529-2908
Foxp3+ regulatory T cells (Treg cells) are the central component of peripheral immune tolerance. Whereas a dysregulated Treg cytokine signature has been observed in autoimmune diseases, the regulatory mechanisms underlying pro- and anti-inflammatory cytokine production are elusive. Here, we identify an imbalance between the cytokines IFN-γ and IL-10 as a shared Treg signature present in patients with multiple sclerosis and under high-salt conditions. RNA-sequencing analysis on human Treg subpopulations revealed β-catenin as a key regulator of IFN-γ and IL-10 expression. The activated β-catenin signature was enriched in human IFN-γ+ Treg cells, as confirmed in vivo with Treg-specific β-catenin-stabilized mice exhibiting lethal autoimmunity with a dysfunctional Treg phenotype. Moreover, we identified prostaglandin E receptor 2 (PTGER2) as a regulator of IFN-γ and IL-10 production under a high-salt environment, with skewed activation of the β-catenin-SGK1-Foxo axis. Our findings reveal a novel PTGER2-β-catenin loop in Treg cells linking environmental high-salt conditions to autoimmunity.
Dominguez-Villar M, Hafler DA, 2018, Regulatory T cells in autoimmune disease, NATURE IMMUNOLOGY, Vol: 19, Pages: 665-673, ISSN: 1529-2908
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- Citations: 313
Pompura SL, Dominguez-Villar M, 2018, The PI3K/AKT signaling pathway in regulatory T-cell development, stability, and function, JOURNAL OF LEUKOCYTE BIOLOGY, Vol: 103, Pages: 1065-1076, ISSN: 0741-5400
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- Citations: 123
Dominguez-Villar M, de Marcken M, Dhaliwal K, 2018, Differential signaling through TLR7 or TLR8 determines the phenotype of human monocytes during RNA virus infection, Annual Meeting of the American-Association-of-Immunologists (AAI), Publisher: AMER ASSOC IMMUNOLOGISTS, ISSN: 0022-1767
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- Citations: 2
Morisse MC, Jouannet S, Dominguez-Villar M, et al., 2018, Interactions between tumor-associated macrophages and tumor cells in glioblastoma: unraveling promising targeted therapies, EXPERT REVIEW OF NEUROTHERAPEUTICS, Vol: 18, Pages: 729-737, ISSN: 1473-7175
Kitz A, Dominguez-Villar M, 2017, Molecular mechanisms underlying Th1-like Treg generation and function, CELLULAR AND MOLECULAR LIFE SCIENCES, Vol: 74, Pages: 4059-4075, ISSN: 1420-682X
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- Citations: 36
Fernandez-Ponce C, Dominguez-Villar M, Munoz-Miranda JP, et al., 2017, Immune modulation by the hepatitis C virus core protein, JOURNAL OF VIRAL HEPATITIS, Vol: 24, Pages: 350-356, ISSN: 1352-0504
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- Citations: 9
Smith LE, Olszewski MA, Georgoudaki A-M, et al., 2016, Sensitivity of dendritic cells to NK-mediated lysis depends on the inflammatory environment and is modulated by CD54/CD226-driven interactions, JOURNAL OF LEUKOCYTE BIOLOGY, Vol: 100, Pages: 781-789, ISSN: 0741-5400
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- Citations: 10
Kitz A, de Marcken M, Gautron A-S, et al., 2016, AKT isoforms modulate Th1-like Treg generation and function in human autoimmune disease, EMBO REPORTS, Vol: 17, Pages: 1169-1183, ISSN: 1469-221X
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- Citations: 59
Bhela S, Kempsell C, Manohar M, et al., 2015, Nonapoptotic and Extracellular Activity of Granzyme B Mediates Resistance to Regulatory T Cell (Treg) Suppression by HLA-DR(-)CD25(hi) CD127(lo) Tregs in Multiple Sclerosis and in Response to IL-6, JOURNAL OF IMMUNOLOGY, Vol: 194, Pages: 2180-2189, ISSN: 0022-1767
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- Citations: 32
Dominguez-Villar M, Gautron A-S, de Marcken M, et al., 2015, TLR7 induces anergy in human CD4(+) T cells, Nature Immunology, Vol: 16, Pages: 118-128, ISSN: 1529-2908
The recognition of microbial patterns by Toll-like receptors (TLRs) is critical for activation of the innate immune system. Although TLRs are expressed by human CD4+ T cells, their function is not well understood. Here we found that engagement of TLR7 in CD4+ T cells induced intracellular calcium flux with activation of an anergic gene-expression program dependent on the transcription factor NFATc2, as well as unresponsiveness of T cells. As chronic infection with RNA viruses such as human immunodeficiency virus type 1 (HIV-1) induces profound dysfunction of CD4+ T cells, we investigated the role of TLR7-induced anergy in HIV-1 infection. Silencing of TLR7 markedly decreased the frequency of HIV-1-infected CD4+ T cells and restored the responsiveness of those HIV-1+ CD4+ T cells. Our results elucidate a previously unknown function for microbial pattern–recognition receptors in the downregulation of immune responses.
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