Imperial College London

DrMargaritaDominguez-Villar

Faculty of MedicineDepartment of Infectious Disease

Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 3735m.dominguez-villar Website

 
 
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Location

 

117Wright Fleming WingSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

45 results found

Dominguez-Villar M, 2022, TKT deficiency puts T-regs to rest, NATURE METABOLISM, Vol: 4, Pages: 503-504

Journal article

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.

Journal article

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.

Journal article

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

Journal article

Pompura SL, Wagner A, Kitz A, LaPerche J, Yosef N, Dominguez-Villar M, Hafler DAet 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

Journal article

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

Journal article

de Marcken M, Dhaliwal K, Danielsen AC, Gautron AS, Dominguez-Villar Met 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.

Journal article

Dominguez-Villar M, Raddassi K, Danielsen AC, Guarnaccia J, Hafler DAet 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

Journal article

Kitz A, de Marcken M, Gautron A-S, Mitrovic M, Hafler DA, Dominguez-Villar Met 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

Journal article

Sumida T, Lincoln MR, Ukeje CM, Rodriguez DM, Akazawa H, Noda T, Naito AT, Komuro I, Dominguez-Villar M, Hafler DAet 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

Journal article

Lucca LE, Axisa P-P, Singer ER, Nolan NM, Dominguez-Villar M, Hafler DAet 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.

Journal article

Dominguez-Villar M, Raddassi K, Danielsen AC, Guarnaccia J, Hafler DAet 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.

Journal article

Sumida T, Lincoln MR, Ukeje CM, Rodriguez DM, Akazawa H, Noda T, Naito AT, Komuro I, Dominguez-Villar M, Hafler DAet 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.

Journal article

Dominguez-Villar M, Hafler DA, 2018, Regulatory T cells in autoimmune disease, NATURE IMMUNOLOGY, Vol: 19, Pages: 665-673, ISSN: 1529-2908

Journal article

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

Journal article

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

Conference paper

Morisse MC, Jouannet S, Dominguez-Villar M, Sanson M, Idbaih Aet 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

Journal article

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

Journal article

Fernandez-Ponce C, Dominguez-Villar M, Munoz-Miranda JP, Arbulo-Echevarria MM, Litran R, Aguado E, Garcia-Cozar Fet al., 2017, Immune modulation by the hepatitis C virus core protein, JOURNAL OF VIRAL HEPATITIS, Vol: 24, Pages: 350-356, ISSN: 1352-0504

Journal article

Smith LE, Olszewski MA, Georgoudaki A-M, Wagner AK, Hagglof T, Karlsson MCI, Dominguez-Villar M, Garcia-Cozar F, Mueller S, Ravens I, Bernhardt G, Chambers BJet 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

Journal article

Kitz A, de Marcken M, Gautron A-S, Mitrovic M, Hafler DA, Dominguez-Villar Met 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

Journal article

Bhela S, Kempsell C, Manohar M, Dominguez-Villar M, Griffin R, Bhatt P, Kivisakk-Webb P, Fuhlbrigge R, Kupper T, Weiner H, Baecher-Allan Cet 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

Journal article

Dominguez-Villar M, Gautron A-S, de Marcken M, Keller MJ, Hafler DAet 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.

Journal article

Nylander A, Dominguez-Villar M, Ramanan S, Hafler DA, Pitt Det al., 2014, Podoplanin is expressed in multiple sclerosis meninges and perivascular infiltrates and regulates T-cell proliferation and Th17 differentiation, Joint ACTRIMS-ECTRIMS Meeting, Publisher: SAGE PUBLICATIONS LTD, Pages: 367-368, ISSN: 1352-4585

Conference paper

Gautron A-S, Dominguez-Villar M, de Marcken M, Hafler DAet al., 2014, Enhanced suppressor function of TIM-3(+)FoxP3(+) regulatory T cells, European Journal of Immunology, Vol: 44, Pages: 2703-2711, ISSN: 0014-2980

T‐cell immunoglobulin and mucin domain 3 (TIM‐3) is an Ig‐superfamily member expressed on IFN‐γ‐secreting Th1 and Tc1 cells and was identified as a negative regulator of immune tolerance. TIM‐3 is expressed by a subset of activated CD4+ T cells, and anti‐CD3/anti‐CD28 stimulation increases both the level of expression and the number of TIM‐3+ T cells. In mice, TIM‐3 is constitutively expressed on natural regulatory T (Treg) cells and has been identified as a regulatory molecule of alloimmunity through its ability to modulate CD4+ T‐cell differentiation. Here, we examined TIM‐3 expression on human Treg cells to determine its role in T‐cell suppression. In contrast to mice, TIM‐3 is not expressed on Treg cells ex vivo but is upregulated after activation. While TIM‐3+ Treg cells with increased gene expression of LAG3, CTLA4, and FOXP3 are highly efficient suppressors of effector T (Teff) cells, TIM‐3− Treg cells poorly suppressed Th17 cells as compared with their suppression of Th1 cells; this decreased suppression ability was associated with decreased STAT‐3 expression and phosphorylation and reduced gene expression of IL10, EBI3, GZMB, PRF1, IL1Rα, and CCR6. Thus, our results suggest that TIM‐3 expression on Treg cells identifies a population highly effective in inhibiting pathogenic Th1‐ and Th17‐cell responses.

Journal article

Kofler DM, Marson A, Dominguez-Villar M, Xiao S, Kuchroo VK, Hafler DAet al., 2014, Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells, Journal of Clinical Investigation, Vol: 124, Pages: 2513-2522, ISSN: 0021-9738

Prostaglandin E2 (PGE2) promotes Th17 expansion while otherwise inhibiting other CD4+ T cell subsets. Here, we identified a PGE2-dependent pathway that induces pathogenic Th17 cells in autoimmune disease and is regulated by the transcription factor RORC. Compared with other CD4+ cell types from healthy subjects, there is a surprising lack of the prostaglandin receptor EP2 on Th17 cells; therefore, we examined the hypothesis that RORγt, which is highly expressed in Th17 cells, mediates EP2 downregulation. Chromatin immunoprecipitation followed by DNA sequencing revealed that RORγt binds directly to Ptger2 (the gene encoding EP2 receptor) in Th17 cells isolated from WT mice. In Th17 cells isolated from humans, RORC repressed EP2 by directly silencing PTGER2 transcription, and knock down of RORC restored EP2 expression in Th17 cells. Compared with Th17 cells from healthy individuals, Th17 cells from patients with MS exhibited reduced RORC binding to the PTGER2 promoter region, resulting in higher EP2 levels and increased expression of IFN-γ and GM-CSF. Finally, overexpression of EP2 in Th17 cells from healthy individuals induced a specific program of inflammatory gene transcription that produced a pathogenic Th17 cell phenotype. These findings reveal that RORC directly regulates the effects of PGE2 on Th17 cells, and dysfunction of this pathway induces a pathogenic Th17 cell phenotype.

Journal article

Fernandez-Ponce C, Dominguez-Villar M, Aguado E, Garcia-Cozar Fet al., 2014, CD4+primary T cells expressing HCV-core protein upregulate Foxp3 and IL-10, suppressing CD4 and CD8 T cells, PLoS ONE, Vol: 9, ISSN: 1932-6203

Adaptive T cell responses are critical for controlling HCV infection. While there is clinical evidence of a relevant role for regulatory T cells in chronic HCV-infected patients, based on their increased number and function; mechanisms underlying such a phenomena are still poorly understood. Accumulating evidence suggests that proteins from Hepatitis C virus can suppress host immune responses. We and others have shown that HCV is present in CD4+ lymphocytes from chronically infected patients and that HCV-core protein induces a state of unresponsiveness in the CD4+ tumor cell line Jurkat. Here we show that CD4+ primary T cells lentivirally transduced with HCV-core, not only acquire an anergic phenotype but also inhibit IL-2 production and proliferation of bystander CD4+ or CD8+ T cells in response to anti-CD3 plus anti-CD28 stimulation. Core-transduced CD4+ T cells show a phenotype characterized by an increased basal secretion of the regulatory cytokine IL-10, a decreased IFN-γ production upon stimulation, as well as expression of regulatory T cell markers, CTLA-4, and Foxp3. A significant induction of CD4+CD25+CD127lowPD-1highTIM-3high regulatory T cells with an exhausted phenotype was also observed. Moreover, CCR7 expression decreased in HCV-core expressing CD4+ T cells explaining their sequestration in inflamed tissues such as the infected liver. This work provides a new perspective on de novo generation of regulatory CD4+ T cells in the periphery, induced by the expression of a single viral protein.

Journal article

Baecher-Allan CM, Manohar M, Bhela S, Kempsell C, Dominguez-Villar M, Fuhlbrigge R, Clark R, Kupper T, Weiner Het al., 2013, Granzyme B plays a central role in delineating subsets and functional differences in human Tregs in blood and skin, International Investigative Dermatology Meeting, Publisher: NATURE PUBLISHING GROUP, Pages: S15-S15, ISSN: 0022-202X

Conference paper

Fernandez Ponce C, Dominguez Villar M, Duran MC, Aguado E, Garcia Cozar Fet al., 2012, Effect of HCV-core expression in CD4(+) primary Lymphocytes, European Congress of Immunology, Publisher: WILEY-BLACKWELL, Pages: 420-420, ISSN: 0019-2805

Conference paper

Dominguez-Villar M, Fernandez-Ponce C, Munoz-Suano A, Gomez E, Rodriguez-Iglesias M, Garcia-Cozar Fet al., 2012, Up-regulation of FOXP3 and induction of suppressive function in CD4(+) Jurkat T-cells expressing hepatitis C virus core protein, CLINICAL SCIENCE, Vol: 123, Pages: 15-27, ISSN: 0143-5221

Journal article

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