Marina Cella

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (120)1185.11 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Although the transcription factor c-Myc is essential for the establishment of a metabolically active and proliferative state in T cells after priming, its expression is transient. It remains unknown how T cell activation is maintained after c-Myc expression is downregulated. Here we identified AP4 as the transcription factor that was induced by c-Myc and sustained activation of antigen-specific CD8(+) T cells. Despite normal priming, AP4-deficient CD8(+) T cells failed to continue transcription of a broad range of c-Myc-dependent targets. Mice lacking AP4 specifically in CD8(+) T cells showed enhanced susceptibility to infection with West Nile virus. Genome-wide analysis suggested that many activation-induced genes encoding molecules involved in metabolism were shared targets of c-Myc and AP4. Thus, AP4 maintains c-Myc-initiated cellular activation programs in CD8(+) T cells to control microbial infection.
    Nature immunology. 07/2014;
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    ABSTRACT: Nfil3 is viewed as an obligate transcription factor for NK cell development. However, mouse CMV (MCMV) infection recently was shown to bypass the requirement for Nfil3 by inducing the appearance of NK cells that express the MCMV-specific receptor Ly49H. Thus, signals transmitted by Ly49H and proinflammatory cytokines are sufficient to promote NK cell differentiation in the absence of Nfil3. In this study, we report that salivary gland (SG) NK cells develop in an Nfil3-independent fashion in the steady-state in the absence of MCMV or any infection. Moreover, we show that SG NK cells have an integrin profile reminiscent of tissue-resident lymphocytes and express TRAIL for killing target cells. These results demonstrate that SG NK cells, although related to conventional NK cells, are a distinct subset of innate lymphoid cells that deviates from the conventional developmental pathway, perhaps under the influence of tissue-specific factors.
    The Journal of Immunology 04/2014; · 5.52 Impact Factor
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    ABSTRACT: The transcription factors c-Myc and N-Myc-encoded by Myc and Mycn, respectively-regulate cellular growth and are required for embryonic development. A third paralogue, Mycl1, is dispensable for normal embryonic development but its biological function has remained unclear. To examine the in vivo function of Mycl1 in mice, we generated an inactivating Mycl1(gfp) allele that also reports Mycl1 expression. We find that Mycl1 is selectively expressed in dendritic cells (DCs) of the immune system and controlled by IRF8, and that during DC development, Mycl1 expression is initiated in the common DC progenitor concurrent with reduction in c-Myc expression. Mature DCs lack expression of c-Myc and N-Myc but maintain L-Myc expression even in the presence of inflammatory signals such as granulocyte-macrophage colony-stimulating factor. All DC subsets develop in Mycl1-deficient mice, but some subsets such as migratory CD103(+) conventional DCs in the lung and liver are greatly reduced at steady state. Importantly, loss of L-Myc by DCs causes a significant decrease in in vivo T-cell priming during infection by Listeria monocytogenes and vesicular stomatitis virus. The replacement of c-Myc by L-Myc in immature DCs may provide for Myc transcriptional activity in the setting of inflammation that is required for optimal T-cell priming.
    Nature 02/2014; · 38.60 Impact Factor
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    ABSTRACT: The transcription factors c-Myc and N-Myc-encoded by Myc and Mycn, respectively-regulate cellular growth and are required for embryonic development. A third paralogue, Mycl1, is dispensable for normal embryonic development but its biological function has remained unclear. To examine the in vivo function of Mycl1 in mice, we generated an inactivating Mycl1(gfp) allele that also reports Mycl1 expression. We find that Mycl1 is selectively expressed in dendritic cells (DCs) of the immune system and controlled by IRF8, and that during DC development, Mycl1 expression is initiated in the common DC progenitor concurrent with reduction in c-Myc expression. Mature DCs lack expression of c-Myc and N-Myc but maintain L-Myc expression even in the presence of inflammatory signals such as granulocyte-macrophage colony-stimulating factor. All DC subsets develop in Mycl1-deficient mice, but some subsets such as migratory CD103(+) conventional DCs in the lung and liver are greatly reduced at steady state. Importantly, loss of L-Myc by DCs causes a significant decrease in in vivo T-cell priming during infection by Listeria monocytogenes and vesicular stomatitis virus. The replacement of c-Myc by L-Myc in immature DCs may provide for Myc transcriptional activity in the setting of inflammation that is required for optimal T-cell priming.
    Nature 02/2014; · 38.60 Impact Factor
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    Marina Cella, Hannah Miller, Christina Song
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    ABSTRACT: For a long time, natural killer (NK) cells were thought to be the only innate immune lymphoid population capable of responding to invading pathogens under the influence of changing environmental cues. In the last few years, an increasing amount of evidence has shown that a number of different innate lymphoid cell (ILC) populations found at mucosal sites rapidly respond to locally produced cytokines in order to establish or maintain homeostasis. These ILC populations closely mirror the phenotype of adaptive T helper subsets in their repertoire of secreted soluble factors. Early in the immune response, ILCs are responsible for setting the stage to mount an adaptive T cell response that is appropriate for the incoming insult. Here, we review the diversity of ILC subsets and discuss similarities and differences between ILCs and NK cells in function and key transcriptional factors required for their development.
    Frontiers in Immunology 01/2014; 5:282.
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    ABSTRACT: Plasmacytoid dendritic cells (pDCs) are a dendritic cell subset that secrete type I IFNs in response to microbial stimuli. The scaffold protein, CD2-associated protein (CD2AP), is a marker of human pDCs as it is highly expressed in this cell type. Recently, in human pDCs, decreased CD2AP expression appeared to enhance the production of type I IFNs via an inhibitory receptor-induced signaling cascade. In this study, we sought to determine the role of CD2AP in murine pDCs using CD2AP knockout (KO) mice. CD2AP was dispensable for the development of pDCs and for the upregulation of activation markers following stimulation. Loss of CD2AP expression did not affect the production of type I IFNs stimulated by TLR ligation, and only slightly impaired type I IFN production when inhibitory pathways were engaged in vitro. This was also confirmed by showing that CD2AP deficiency did not influence type I IFN production by pDCs in vivo. Because CD2AP plays a role in regulating actin dynamics, we examined the actin cytoskeleton in pDCs and found that activated CD2AP KO pDCs had significantly higher levels of actin polymerization than wild-type pDCs. Using two different inflammation models, we found that CD2AP KO pDCs have a defect in lymph node migration, correlating with the defects in actin dynamics. Our work excludes a role for CD2AP in the regulation of type I IFNs in pDCs, and suggests that the major function of CD2AP is on the actin cytoskeleton, affecting migration to local lymph nodes under conditions of inflammation.
    The Journal of Immunology 11/2013; · 5.52 Impact Factor
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    ABSTRACT: Viruses have long been studied not only for their pathology and associated disease but also as model systems for understanding cellular and immunological processes. Rodent herpesvirus Peru (RHVP) is a recently characterized rhadinovirus related to murine gammaherpesvirus 68 (MHV68) and Kaposi's sarcoma-associated herpesvirus (KSHV) that establishes acute and latent infection in laboratory mice. RHVP encodes numerous unique proteins that we hypothesize might facilitate host immune evasion during infection. We report here that ORF R17 encodes a high affinity chemokine binding protein that broadly recognizes human and murine CC-and C-chemokines. The interaction of R17 with chemokines is generally characterized by rapid association kinetics, and in the case of CCL3, CCL4, CCL5, CCL24, and XCL1, extremely stable complexes are formed. Functionally, R17 potently inhibited CCL2 driven chemotaxis of the human monocytic cell line THP-1, CCL3 driven chemotaxis of peripheral blood mononuclear cells, and CCL2 mediated calcium flux. Our studies also reveal that R17 binds to glycosaminoglycans (GAGs) in a process dependent upon two BBXB motifs, and that chemokine and GAG binding can occur simultaneously at distinct sites. Collectively, these studies suggest that R17 may play a role in RHVP immune evasion through the targeted sabotage of chemokine mediated immune surveillance.
    Journal of Virology 10/2013; · 5.08 Impact Factor
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    ABSTRACT: BACKGROUND & AIMS: An increased number of macrophages in adipose tissue is associated with insulin resistance and metabolic dysfunction in obese people. However, little is known about other immune cells in adipose tissue from obese people, and whether they contribute to insulin resistance. We investigated the characteristics of T cells in adipose tissue from metabolically abnormal insulin-resistant obese (MAO), metabolically normal insulin-sensitive obese (MNO), and lean subjects. Insulin sensitivity was determined by using the hyperinsulinemic euglycemicclamp procedure. METHODS: We assessed plasma cytokine concentrations and subcutaneous adipose tissue CD4(+) T-cell populations in 9 lean, 12 MNO, and 13 MAO subjects. Skeletal muscle and liver samples were collected from 19 additional obese patients undergoing bariatric surgery, to determine the presence of selected cytokine receptors. RESULTS: Adipose tissue from MAO subjects had 3- to 10-fold increases in numbers of CD4(+) T cells that produce IL-22 and IL-17 (a T-helper [Th] 17 and Th22 phenotype), compared with MNO and lean subjects. MAO subjects also had increased plasma concentrations of IL-22 and IL-6. Receptors for IL-17 and IL-22 were expressed in human liver and skeletal muscle samples. IL-17 and IL-22 inhibited uptake of glucose in skeletal muscle isolated from rats and reduced insulin sensitivity in cultured human hepatocytes. CONCLUSIONS: Adipose tissue from MAO individuals contains increased numbers of Th17 and Th22 cells, which produce cytokines that cause metabolic dysfunction in liver and muscle in vitro. Additional studies are needed to determine whether these alterations in adipose tissue T cells contribute to the pathogenesis of insulin resistance in obese people.
    Gastroenterology 04/2013; · 12.82 Impact Factor
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    ABSTRACT: Mucosal innate lymphoid cell (ILC) subsets promote immune responses to pathogens by producing distinct signature cytokines in response to changes in the cytokine microenvironment. We previously identified human ILC3 distinguished by interleukin-22 (IL-22) secretion. Here we characterized a human ILC1 subset that produced interferon-γ (IFN-γ) in response to IL-12 and IL-15 and had a unique integrin profile, intraepithelial location, hallmarks of TGF-β imprinting, and a memory-activated phenotype. Because tissue-resident memory CD8+ T cells share this profile, intraepithelial ILC1 may be their innate counterparts. In mice, intraepithelial ILC1 were distinguished by CD160 expression and required Nfil3- and Tbx21-encoded transcription factors for development, but not IL-15 receptor-α, indicating that intraepithelial ILC1 are distinct from conventional NK cells. Intraepithelial ILC1 were amplified in Crohn's disease patients and contributed to pathology in the anti-CD40-induced colitis model in mice. Thus, intraepithelial ILC1 may initiate IFN-γ responses against pathogens but contribute to pathology when dysregulated.
    Immunity 02/2013; · 19.80 Impact Factor
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    ABSTRACT: The differentiation of bone marrow-derived progenitor cells into monocytes, tissue macrophages and some dendritic cell (DC) subtypes requires the growth factor CSF1 and its receptor, CSF1R. Langerhans cells (LCs) and microglia develop from embryonic myeloid precursor cells that populate the epidermis and central nervous system (CNS) before birth. Notably, LCs and microglia are present in CSF1-deficient mice but absent from CSF1R-deficient mice. Here we investigated whether an alternative CSF1R ligand, interleukin 34 (IL-34), is responsible for this discrepancy. Through the use of IL-34-deficient (Il34(LacZ/LacZ)) reporter mice, we found that keratinocytes and neurons were the main sources of IL-34. Il34(LacZ/LacZ) mice selectively lacked LCs and microglia and responded poorly to skin antigens and viral infection of the CNS. Thus, IL-34 specifically directs the differentiation of myeloid cells in the skin epidermis and CNS.
    Nature Immunology 06/2012; 13(8):753-60. · 26.20 Impact Factor
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    ABSTRACT: Type I interferon (IFN-I) promotes antiviral CD8(+)T cell responses, but the contribution of different IFN-I sources and signaling pathways are ill defined. While plasmacytoid dendritic cells (pDCs) produce IFN-I upon TLR stimulation, IFN-I is induced in most cells by helicases like MDA5. Using acute and chronic lymphocytic choriomeningitis virus (LCMV) infection models, we determined that pDCs transiently produce IFN-I that minimally impacts CD8(+)T cell responses and viral persistence. Rather, MDA5 is the key sensor that induces IFN-I required for CD8(+)T cell responses. In the absence of MDA5, CD8(+)T cell responses to acute infection rely on CD4(+)T cell help, and loss of both CD4(+)T cells and MDA5 results in CD8(+)T cell exhaustion and persistent infection. Chronic LCMV infection rapidly attenuates IFN-I responses, but early administration of exogenous IFN-I rescues CD8(+)T cells, promoting viral clearance. Thus, effective antiviral CD8(+)T cell responses depend on the timing and magnitude of IFN-I production.
    Cell host & microbe 06/2012; 11(6):631-42. · 13.02 Impact Factor
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    ABSTRACT: TREM2 is an immunoreceptor expressed on osteoclasts (OC) and microglia that transmits intracellular signals through the adaptor DAP12. Individuals with genetic mutations inactivating TREM2 or DAP12 develop the Nasu-Hakola disease (NHD) with cystic-like lesions of the bone and brain demyelination that lead to fractures and presenile dementia. The mechanisms of this disease are poorly understood. In this study, we report that TREM2-deficient mice have an osteopenic phenotype reminiscent of NHD. In vitro, lack of TREM2 impairs proliferation and β-catenin activation in osteoclast precursors (OcP) in response to M-CSF. This defect results in accelerated differentiation of OcP into mature OC. Corroborating the importance of a balanced proliferation and differentiation of OcP for bone homeostasis, we show that conditional deletion of β-catenin in OcP also results in reduced OcP proliferation and accelerated osteoclastogenesis in vitro as well as osteopenia in vivo. These results reveal that TREM2 regulates the rate of osteoclastogenesis and provide a mechanism for the bone pathology in NHD.
    The Journal of Immunology 03/2012; 188(6):2612-21. · 5.52 Impact Factor
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    ABSTRACT: Macrophages are essential in atherosclerosis progression, but regulation of the M1 versus M2 phenotype and their role in cholesterol deposition are unclear. We demonstrate that endoplasmic reticulum (ER) stress is a key regulator of macrophage differentiation and cholesterol deposition. Macrophages from diabetic patients were classically or alternatively stimulated and then exposed to oxidized LDL. Alternative stimulation into M2 macrophages lead to increased foam cell formation by inducing scavenger receptor CD36 and SR-A1 expression. ER stress induced by alternative stimulation was necessary to generate the M2 phenotype through JNK activation and increased PPARγ expression. The absence of CD36 or SR-A1 signaling independently of modified cholesterol uptake decreased ER stress and prevented the M2 differentiation typically induced by alternative stimulation. Moreover, suppression of ER stress shifted differentiated M2 macrophages toward an M1 phenotype and subsequently suppressed foam cell formation by increasing HDL- and apoA-1-induced cholesterol efflux indicating suppression of macrophage ER stress as a potential therapy for atherosclerosis.
    Journal of Biological Chemistry 02/2012; 287(15):11629-41. · 4.65 Impact Factor
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    Jacob S Lee, Marina Cella, Marco Colonna
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    ABSTRACT: Mucosal innate lymphoid cells (ILCs) are an emerging population of diverse and heterogeneous immune cells, all with the unique ability to mount a rapid response against invading pathogens. They are further divided into subsets based on their differing cell surface markers as well as in their functional specialization. In this review, we summarize recent reports describing the importance of the transcription factor aryl hydrocarbon receptor (AHR) in regulating the development of one of these subsets, the Type-17/22 ILCs, as well as in the organization of postnatal lymphoid structures. We discuss the mechanisms behind the AHR dependence for development in Type-17/22 ILCs as well as reviewing the proposed physiological ligands that are mediating this effect.
    Frontiers in Immunology 01/2012; 3:10.
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    ABSTRACT: Innate lymphoid cells (ILCs) of the ILC22 type protect the intestinal mucosa from infection by secreting interleukin 22 (IL-22). ILC22 cells include NKp46(+) and lymphoid tissue-inducer (LTi)-like subsets that express the aryl hydrocarbon receptor (AHR). Here we found that Ahr(-/-) mice had a considerable deficit in ILC22 cells that resulted in less secretion of IL-22 and inadequate protection against intestinal bacterial infection. Ahr(-/-) mice also lacked postnatally 'imprinted' cryptopatches and isolated lymphoid follicles (ILFs), but not embryonically 'imprinted' Peyer's patches. AHR induced the transcription factor Notch, which was required for NKp46(+) ILCs, whereas LTi-like ILCs, cryptopatches and ILFs were partially dependent on Notch signaling. Thus, AHR was essential for ILC22 cells and postnatal intestinal lymphoid tissues. Moreover, ILC22 subsets were heterogeneous in their requirement for Notch and their effect on the generation of intestinal lymphoid tissues.
    Nature Immunology 11/2011; 13(2):144-51. · 26.20 Impact Factor
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    ABSTRACT: Osteoclasts are terminally differentiated leukocytes that erode the mineralized bone matrix. Osteoclastogenesis requires costimulatory receptor signaling through adaptors containing immunoreceptor tyrosine-based activation motifs (ITAMs), such as Fc receptor common γ (FcRγ) and DNAX-activating protein of 12 kDa. Identification of these ITAM-containing receptors and their ligands remains a high research priority, since the stimuli for osteoclastogenesis are only partly defined. Osteoclast-associated receptor (OSCAR) was proposed to be a potent FcRγ-associated costimulatory receptor expressed by preosteoclasts in vitro, but OSCAR lacks a cognate ligand and its role in vivo has been unclear. Using samples from mice and patients deficient in various ITAM signaling pathways, we show here that OSCAR costimulates one of the major FcRγ-associated pathways required for osteoclastogenesis in vivo. Furthermore, we found that OSCAR binds to specific motifs within fibrillar collagens in the ECM that become revealed on nonquiescent bone surfaces in which osteoclasts undergo maturation and terminal differentiation in vivo. OSCAR promoted osteoclastogenesis in vivo, and OSCAR binding to its collagen motif led to signaling that increased numbers of osteoclasts in culture. Thus, our results suggest that ITAM-containing receptors can respond to exposed ligands in collagen, leading to the functional differentiation of leukocytes, which provides what we believe to be a new concept for ITAM regulation of cytokine receptors in different tissue microenvironments.
    The Journal of clinical investigation 08/2011; 121(9):3505-16. · 15.39 Impact Factor
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    ABSTRACT: Immature dendritic cells (DCs) specialize in antigen capture and maintain a highly dynamic pool of intracellular major histocompatibility complex class II (MHCII) that continuously recycles from peptide loading compartments to the plasma membrane and back again. This process facilitates sampling of environmental antigens for presentation to T helper cells. Here, we show that a signaling pathway mediated by the DC immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptors (DAP12 and FcRγ) and Vav family guanine nucleotide exchange factors controls the half-life of surface peptide-MHCII (pMHCII) complexes and is critical for CD4 T-cell triggering in vitro. Strikingly, mice with disrupted DC ITAMs show defective T helper cell priming in vivo and are protected from experimental autoimmune encephalitis. Mechanistically, we show that deficiency in ITAM signaling results in increased pMHCII internalization, impaired recycling, and an accumulation of ubiquitinated MHCII species that are prematurely degraded in lysosomes. We propose a novel mechanism for control of T helper cell priming.
    Blood 10/2010; 116(17):3208-18. · 9.78 Impact Factor
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    Marina Cella, Karel Otero, Marco Colonna
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    ABSTRACT: Natural killer-22 (NK-22) cells are a human NK cell subset situated in mucosal-associated lymphoid tissues that specialize in IL-22 secretion in response to IL-23. Here we investigated the cytokine requirements for NK-22 cell expansion. IL-7 maintained the survival of NK-22 cells and IL-22 production in response to IL-23 but was insufficient to induce robust expansion. Proliferation of NK-22 cells was increased markedly by adding either IL-1beta or IL-2 to IL-7 and was even stronger in the presence of IL-1beta plus IL-2. In contrast to IL-7, continuous culture in IL-1beta and IL-2 modified NK-22 cytokine profiles. IL-1beta promoted constitutive IL-22 secretion rather than acute IL-22 production in response to IL-23 and induced IL-17 in some cells. IL-2 reduced secretion of IL-22 and IL-17, increasing production of IFN-gamma and leukemia inhibitory factor. Functional deviation toward IFN-gamma production also was induced by continuous culture in IL-23. These results demonstrate the functional plasticity of NK-22 cells, which may allow flexible responses to different pathogens. Finally, we found that NK-22 cells released the B-cell survival factor, B-cell activating factor belonging to the TNF family (BAFF), suggesting a potential role of NK-22 cells in promoting B-cell-mediated mucosal immunity.
    Proceedings of the National Academy of Sciences 06/2010; 107(24):10961-6. · 9.81 Impact Factor
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    ABSTRACT: The hallmark of chronic viral infections is a progressive exhaustion of antigen-specific CD8(+) T cells that leads to persisting viral replication. It is generally believed that exhaustion is a consequence of the accumulation of multiple inhibitory receptors on CD8(+) T cells that makes them dysfunctional. Here, we show that during human chronic HIV-1 infection, a CD8(+) T-cell positive costimulatory pathway mediated by DNAX-activating molecule-1 is also disrupted. Thus, DNAX-activating molecule-1 downregulation on CD8(+) T cells aggravates the impairment of CTL effector function in chronic HIV-1 infection.
    European Journal of Immunology 03/2010; 40(4):949-54. · 4.97 Impact Factor
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    ABSTRACT: Polyinosinic:polycytidylic acid (poly I:C), a synthetic analog of double-stranded viral RNA, serves as a potent adjuvant for vaccination against soluble proteins, pathogens, and tumors. Poly I:C is sensed by both TLR3 in the endosomes and melanoma differentiation-associated protein 5 (MDA5) in the cytoplasm. Although it is known that TLR3 is required for cross-priming of CD8 T cells specific for viral Ags, the role of MDA5 in inducing CD8 T cell responses is still unclear. In this study, we demonstrate that in mice lacking MDA5, the majority of CD8 T cells do not survive after primary immunization with poly I:C and Ag, impairing memory response to subsequent Ag challenge. Furthermore, bone marrow chimera experiments revealed that MDA5 expression in radiation-resistant stromal cells, but not in radiation-sensitive hematopoietic cells, is essential for establishing CD8 T cell memory. We conclude that MDA5 and TLR3 mediate substantially distinct yet complementary functions during poly I:C-mediated activation of Ag-specific CD8 T cell responses.
    The Journal of Immunology 02/2010; 184(6):2751-5. · 5.52 Impact Factor

Publication Stats

16k Citations
1,185.11 Total Impact Points

Institutions

  • 2001–2014
    • Washington University in St. Louis
      • Department of Pathology and Immunology
      San Luis, Missouri, United States
    • IT University of Copenhagen
      København, Capital Region, Denmark
  • 2002–2013
    • University of Washington Seattle
      • Department of Immunology
      Seattle, WA, United States
  • 2012
    • Central Arkansas Veterans Healthcare System
      Washington, Washington, D.C., United States
  • 2009
    • University of Nebraska Medical Center
      Omaha, Nebraska, United States
  • 2008
    • Tohoku University
      • Institute of Development, Aging and Cancer
      Sendai, Kagoshima, Japan
  • 2003
    • Università degli Studi di Brescia
      • Department of Clinical and Experimental Sciences
      Brescia, Lombardy, Italy
    • University of Texas Health Science Center at San Antonio
      • Department of Microbiology and Immunology
      San Antonio, Texas, United States