Sonia Feau

La Jolla Institute for Allergy & Immunology, La Jolla, California, United States

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Publications (16)192.61 Total impact

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    ABSTRACT: Adaptive immune responses to Ags released by dying cells play a critical role in the development of autoimmunity, allograft rejection, and spontaneous as well as therapy-induced tumor rejection. Although cell death in these situations is considered sterile, various reports have implicated type I IFNs as drivers of the ensuing adaptive immune response to cell-associated Ags. However, the mechanisms that underpin this type I IFN production are poorly defined. In this article, we show that dendritic cells (DCs) can uptake and sense nuclear DNA-associated entities released by dying cells to induce type I IFN. Remarkably, this molecular pathway requires STING, but not TLR or NLR function, and results in the activation of IRF3 in a TBK1-dependent manner. DCs are shown to depend on STING function in vivo to efficiently prime IFN-dependent CD8(+) T cell responses to tumor Ags. Furthermore, loss of STING activity in DCs impairs the generation of follicular Th cells and plasma cells, as well as anti-nuclear Abs, in an inducible model of systemic lupus erythematosus. These findings suggest that the STING pathway could be manipulated to enable the rational design of immunotherapies that enhance or diminish antitumor and autoimmune responses, respectively.
    The Journal of Immunology 11/2014; 193(12). DOI:10.4049/jimmunol.1401869
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    ABSTRACT: The generation of CD8(+) T cells by vaccination represents an important goal for protective immunity to infectious pathogens. It is thus of utmost importance to understand the mechanisms involved in the generation of optimal CD8(+) T-cell responses. The forkhead box O (FoxO) family of transcription factors has a crucial role in cellular responses to environmental change. Among them, FoxO3 is critically involved in the regulation of cellular proliferation, apoptosis, metabolism and stress resistance to withdrawal of nutrients or cytokine growth factors. Since the role of FoxO3 has been poorly studied in the immune system, here we have evaluated its involvement in the CD8(+) T-cell response. We observe that CD8(+) T cells deficient for FoxO3 undergo a significantly greater primary expansion than their wild-type (WT) counterparts in response to both infectious (vaccinia virus) or non-infectious (non-replicating cellular vaccine) immunogens, resulting in a larger cohort of cells following contraction. These survivors, however, do not undergo a greater secondary response than WT. Taken together, our data show that FoxO3 is a negative regulator of the CD8(+) T-cell response, specifically during the primary expansion.Immunology and Cell Biology advance online publication, 23 September 2014; doi:10.1038/icb.2014.78.
    Immunology and Cell Biology 09/2014; 93(2). DOI:10.1038/icb.2014.78
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    ABSTRACT: Mucosal dendritic cells (DCs) in the intestine acquire the unique capacity to produce retinoic acid (RA), a vitamin A metabolite that induces gut tropism and regulates the functional differentiation of the T cells they prime. Here, we identified a stromal cell (SC) population in the intestinal lamina propria (LP), which is capable of inducing RA production in DCs in a RA- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent fashion. Unlike DCs, LP SCs constitutively expressed the enzymatic machinery to produce RA even in the absence of dietary vitamin A, but were not able to do so in germ-free mice implying regulation by microbiota. Interestingly, DCs promoted GM-CSF production by the SCs indicating a two-way cross-talk between both cell types. Furthermore, RA-producing LP SCs and intestinal DCs localized closely in vivo suggesting that the interactions between both cell types might have an important role in the functional education of migratory DCs and therefore in the regulation of immune responses toward oral and commensal antigens.Mucosal Immunology advance online publication, 18 June 2014; doi:10.1038/mi.2014.51.
    Mucosal Immunology 06/2014; 8(1). DOI:10.1038/mi.2014.51
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    ABSTRACT: After antigenic stimulation, CD8(+) T cells undergo clonal expansion and differentiation into CTLs that can mount a strong defense against intracellular pathogens and tumors. SWAP-70-like adapter of T cells (SLAT), also known as Def6, is a novel guanine nucleotide exchange factor for the Cdc42 GTPase and plays a role in CD4(+) T cell activation and Th cell differentiation by controlling Ca(2+)/NFAT signaling, but its requirement in CD8(+) T cell response has not been explored. Using a range of transgenic and knockout in vivo systems, we show that SLAT is required for efficient expansion of CD8(+) T cells during the primary response but is not necessary for CTL differentiation. The reduced clonal expansion observed in the absence of SLAT resulted from a CD8(+) T cell-intrinsic proliferation defect and a reduced IL-2-dependent cell survival. On a molecular level, we show that Def6 deficiency resulted in defective TCR/CD28-induced NFAT translocation to the nucleus in CD8(+) T cells. Constitutively active Cdc42 or NFAT1 mutants fully restored the impaired expansion of Def6(-/-) CD8(+) T cells. Taken together, these data describe a new and pivotal role of SLAT-mediated NFAT activation in CD8(+) T cells, providing new insight into the signaling pathways involved in CD8(+) T cell proliferation.
    The Journal of Immunology 11/2012; 190(1). DOI:10.4049/jimmunol.1201685
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    ABSTRACT: CD8(+) cytotoxic T lymphocytes are critical components of immunity against infectious pathogens, tumours, and in the case of pathogenic autoimmunity, normal self tissues. CD4(+) T (T(H)) cells provide 'help' to CD8(+) cytotoxic T lymphocytes during priming by first activating antigen-presenting cells via CD40-CD40L interactions. Here we show that, after immunization with either a noninflammatory, nonreplicating antigen or an overtly inflammatory replicating antigen, CD8(+) cytotoxic T lymphocytes prevented from receiving a signal through CD27 during priming subsequently exhibit a specific defect in their capacity for secondary expansion that can be rescued by the absence of TRAIL. Thus, the 'help message' is transmitted to CD8(+) T cells via CD70-CD27 signals, enabling them to undergo secondary expansion and avoid TRAIL-mediated apoptosis on re-stimulation. These findings complete our understanding of the cellular interactions through which T(H) is provided to CD8(+) cytotoxic T lymphocytes during priming.
    Nature Communications 07/2012; 3:948. DOI:10.1038/ncomms1948
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    ABSTRACT: Two competing theories have been put forward to explain the role of CD4(+) T cells in priming CD8(+) memory T cells: one proposes paracrine secretion of interleukin 2 (IL-2); the other proposes the activation of antigen-presenting cells (APCs) via the costimulatory molecule CD40 and its ligand CD40L. We investigated the requirement for IL-2 by the relevant three cell types in vivo and found that CD8(+) T cells, rather than CD4(+) T cells or dendritic cells (DCs), produced the IL-2 necessary for CD8(+) T cell memory. Il2(-/-) CD4(+) T cells were able to provide help only if their ability to transmit signals via CD40L was intact. Our findings reconcile contradictory elements implicit in each model noted above by showing that CD4(+) T cells activate APCs through a CD40L-dependent mechanism to enable autocrine production of IL-2 in CD8(+) memory T cells.
    Nature Immunology 07/2011; 12(9):908-13. DOI:10.1038/ni.2079
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    ABSTRACT: A new report in Immunity shows that, rather than driving the metabolic changes required for proliferation, Akt controls the gene expression programs that determine whether activated CD8+ T cells differentiate into memory or effector cells.
    Immunity 02/2011; 34(2):141-3. DOI:10.1016/j.immuni.2011.02.013
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    ABSTRACT: T cells that respond quickly to infection and later to reinfection arise from a single precursor cell type.
    Science 02/2009; 323(5913):466-7. DOI:10.1126/science.1169409
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    ABSTRACT: SWAP-70-like adaptor of T cells (SLAT) is a guanine nucleotide exchange factor for Rho GTPases that regulates the development of T helper 1 (Th1) and Th2 cell inflammatory responses by controlling the Ca(2+)-NFAT signaling pathway. However, the mechanism used by SLAT to regulate these events is unknown. Here, we report that the T cell receptor (TCR)-induced translocation of SLAT to the immunological synapse required Lck-mediated phosphorylation of two tyrosine residues located in an immunoreceptor tyrosine-based activation motif-like sequence but was independent of the SLAT PH domain. This subcellular relocalization was coupled to, and necessary for, activation of the NFAT pathway. Furthermore, membrane targeting of the SLAT Dbl-homology (catalytic) domain was sufficient to trigger TCR-mediated NFAT activation and Th1 and Th2 differentiation in a Cdc42-dependent manner. Therefore, tyrosine-phosphorylation-mediated relocalization of SLAT to the site of antigen recognition is required for SLAT to exert its pivotal role in NFAT-dependent CD4(+) T cell differentiation.
    Immunity 12/2008; 29(5):704-19. DOI:10.1016/j.immuni.2008.08.015
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    ABSTRACT: Dendritic cells (DCs) are involved in the initiation and regulation of innate and adaptive immune responses. Several molecular mechanisms regulate these diverse DC functions, and we have previously reported that mouse dendritic cells (mDCs) can produce interleukin-2 (IL-2) in vitro and in vivo, in response to microbial activation and T-cell-mediated stimuli. This property is shared by different DC subtypes, including Langerhans cells. Here we show that, on appropriate stimulation, human DCs, both plasmacytoid and myeloid subtypes, also express IL-2. Interestingly, the production of IL-2 by myeloid DCs is induced by T-cell-mediated stimuli and depends on the presence of IL-15. The key role of this cytokine in regulating IL-2 production was also confirmed in the mouse system. In particular, we could show that DCs from IL-15-deficient mice were strongly impaired in the ability to produce IL-2 after interactions with different microbial stimuli. Our results indicate that DC-produced IL-2 is tightly coregulated with the expression of IL-15.
    Blood 02/2005; 105(2):697-702. DOI:10.1182/blood-2004-03-1059
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    ABSTRACT: Dendritic cells (DCs) are key regulators of immune reactions. They control early innate responses, regulate long-lasting adaptive immunity and contribute to the maintenance of self-tolerance. DCs continuously monitor the environment through a multifaceted innate antigen receptor repertoire and, in response to perturbations, start a complex genetic reprogramming that leads to a complete activation of innate and, then, adaptive immune responses. This review discusses how DCs become efficient activators of NK and, subsequently, T cells following a microbial encounter.
    International Archives of Allergy and Immunology 08/2004; 134(3):179-85. DOI:10.1159/000078764
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    ABSTRACT: The immune system of vertebrate animals is characterized by the capacity to respond to disturbances. This function requires 2 different approaches. First, the immune system responds in a few hours to infectious agents (innate immunity) by recognizing molecular patterns typical of microorganisms (but absent in self-tissues). Second, it mounts a late response that differentiates among different microbes, giving rise to memory (adaptive immunity). In this context, dendritic cells (DCs) play a central role, becoming efficient stimulators of both innate and adaptive responses after microbial activation. Recent data generated by global transcriptional profiling of DCs after bacterial encounter are discussed, as are the unique DC functional plasticity and the central role of DC-derived interleukin-2 in priming early and late immune responses.
    The Journal of Infectious Diseases 07/2003; 187 Suppl 2:S346-50. DOI:10.1086/374748
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    ABSTRACT: Dendritic cells are professional antigen-presenting cells able to initiate innate and adaptive immune responses against invading pathogens. In response to external stimuli dendritic cells undergo a complete genetic reprogramming that allows them to become, soon after activation, natural killer cell activators and subsequently T cell stimulators. The recent observation that dendritic cells produce interleukin 2 following microbial stimulation opens new possibilities for understanding the efficiency of dendritic cells in regulating immune system functions. This review discusses how dendritic cells control natural killer, T- and B-cell responses and the relevance of interleukin 2 in these processes.
    The EMBO Journal 07/2003; 22(11):2546-51. DOI:10.1093/emboj/cdg261
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    ABSTRACT: Dendritic cells (DCs) are professional APCs able to initiate innate and adaptive immune responses against invading pathogens. Different properties such as the efficient Ag processing machinery, the high levels of expression of costimulatory molecules and peptide-MHC complexes, and the production of cytokines contribute in making DCs potent stimulators of naive T cell responses. Recently we have observed that DCs are able to produce IL-2 following bacterial stimulation, and we have demonstrated that this particular cytokine is a key molecule conferring to early bacterial activated DCs unique T cell priming capacity. In the present study we show that many different microbial stimuli, but not inflammatory cytokines, are able to stimulate DCs to produce IL-2, indicating that DCs can distinguish a cytokine-mediated inflammatory process from the actual presence of an infection. The capacity to produce IL-2 following a microbial stimuli encounter is a feature shared by diverse DC subtypes in vivo, such as CD8 alpha(+) and CD8 alpha(-) splenic DCs and epidermal Langerhans cells. When early activated DCs interact with T cells, IL-2 produced by DCs is enriched at the site of cell-cell contact, confirming the importance of DCs-derived IL-2 in T cell activation.
    The Journal of Immunology 06/2003; 170(10):5075-81. DOI:10.4049/jimmunol.170.10.5075
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    ABSTRACT: The T-cell repertoire developing in the thymus is rid of autospecific cells by the process of thymic negative selection. Recognition of major histocompatibility complex (MHC)/self-peptide complexes expressed by thymic antigen-presenting cells (APC) of bone marrow origin leads to induction of apoptotic death of autospecific thymocytes. Induction of tolerance to self-antigens not presented by thymic APC is mediated by medullary thymic epithelial cells (mTEC) which express a very wide range of proteins, e.g. inducible and tissue-specific proteins. The main type of tolerance induced by mTEC is non-deletional and the issue of how it is maintained outside the thymus is therefore of crucial interest. We have previously shown that the non-T-cell receptor (TCR) -transgenic T-cell repertoire developing in conditions in which tolerance to self-MHC/peptide ligands is exclusively induced by mTEC is tolerant to syngeneic targets in vivo but lyses such targets in vitro. Here we report that this non-deletional in vivo self-tolerance is not due to active tolerance assured by known naturally occurring regulatory or immune-modulating T lymphocytes. Importantly, we show that in vivo maintenance of this therefore probably anergic state requires continued interaction of autospecific T cells with self-MHC/peptide ligands expressed by radioresistant cells while APC are incapable of maintaining the tolerant state. Therefore, maintenance of non-deletional T-lymphocyte tolerance to the wide range of self-antigens expressed by mTEC depends on continued interaction with radioresistant cells that very probably express a much more limited repertoire of antigens. Our data may therefore have important consequences for tolerance to tissue-specific and inducible self-antigens.
    Immunology 02/2003; 108(1):24-31. DOI:10.1046/j.1365-2567.2003.01546.x
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    ABSTRACT: Dendritic cells (DCs) are strong activators of primary T cell responses. Their priming ability is acquired upon encounter with maturation stimuli. To identify the genes that are differentially expressed upon maturation induced by exposure to Gram-negative bacteria, a kinetic study of DC gene expression was done with microarrays representing 11,000 genes and ESTs (expressed sequence tags). Approximately 3000 differentially expressed transcripts were identified. We found that functional interleukin 2 (IL-2) mRNA, which gave rise to IL-2 production, was transiently up-regulated at early time-points after bacterial encounter. In contrast, macrophages did not produce IL-2 upon bacterial stimulation. Thus, IL-2 is an additional key cytokine that confers unique T cell stimulatory capacity to DCs.
    Nature Immunology 10/2001; 2(9):882-8. DOI:10.1038/ni0901-882

Publication Stats

723 Citations
192.61 Total Impact Points

Institutions

  • 2008–2014
    • La Jolla Institute for Allergy & Immunology
      • Division of Developmental Immunology
      La Jolla, California, United States
  • 2001–2005
    • Università degli Studi di Milano-Bicocca
      • Department of Biotechnology and Biosciences
      Milano, Lombardy, Italy
  • 2003
    • French Institute of Health and Medical Research
      • Toulouse Purpan Pathophysiology Center CPTP
      Lutetia Parisorum, Île-de-France, France