Terri M Laufer

University of Pennsylvania, Filadelfia, Pennsylvania, United States

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Publications (62)631.34 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Inflammatory CD4(+) T cell responses to self or commensal bacteria underlie the pathogenesis of autoimmunity and inflammatory bowel disease (IBD), respectively. While selection of self-specific T cells in the thymus limits responses to mammalian tissue antigens, the mechanisms that control selection of commensal bacteria-specific T cells remain poorly understood. Here, we demonstrate that group 3 innate lymphoid cell (ILC3)-intrinsic expression of major histocompatibility complex class II (MHCII) is regulated similarly to thymic epithelial cells and that MHCII(+) ILC3s directly induce cell death of activated commensal bacteria-specific T cells. Further, MHCII on colonic ILC3s was reduced in pediatric IBD patients. Collectively, these results define a selection pathway for commensal bacteria-specific CD4(+) T cells in the intestine and suggest that this process is dysregulated in human IBD. Copyright © 2015, American Association for the Advancement of Science.
    Science 04/2015; 348(6238). DOI:10.1126/science.aaa4812 · 31.48 Impact Factor
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    ABSTRACT: Regulatory T cells (Tregs) are CD4(+) T cells that maintain immune homeostasis and prevent autoimmunity. Like all CD4(+) T cells, Tregs require antigen-specific signals via T cell receptor-major histocompatibility complex class II (TCR-MHCII) interactions for their development. However, the requirement for MHCII in Treg homeostasis in tissues such as intestinal lamina propria (LP) is unknown. We examined LP Treg homeostasis in a transgenic mouse model that lacks peripheral TCR-MHCII interactions and generation of extrathymic Tregs (iTregs). Thymically generated Tregs entered the LP of weanlings and proliferated independently of MHCII to fill the compartment. The adult LP was a closed niche; new thymic Tregs were excluded, and Tregs in parabiotic pairs were LP resident. The isolated LP niche was interleukin-2 (IL-2) independent but dependent on commensal bacteria. Thus, an LP Treg niche can be filled, isolated, and maintained independently of antigen signals and iTregs. This niche may represent a tissue-specific mechanism for maintaining immune tolerance. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 12/2014; 9(5). DOI:10.1016/j.celrep.2014.11.006 · 7.21 Impact Factor
  • Taku Kambayashi, Terri M Laufer
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    ABSTRACT: Dendritic cells, macrophages and B cells are regarded as the classical antigen-presenting cells of the immune system. However, in recent years, there has been a rapid increase in the number of cell types that are suggested to present antigens on MHC class II molecules to CD4(+) T cells. In this Review, we describe the key characteristics that define an antigen-presenting cell by examining the functions of dendritic cells. We then examine the functions of the haematopoietic cells and non-haematopoietic cells that can express MHC class II molecules and that have been suggested to represent 'atypical' antigen-presenting cells. We consider whether any of these cell populations can prime naive CD4(+) T cells and, if not, question the effects that they do have on the development of immune responses.
    Nature reviews. Immunology 10/2014; 14(11). DOI:10.1038/nri3754 · 33.84 Impact Factor
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    ABSTRACT: How commensal microbiota contributes to immune cell homeostasis at barrier surfaces is poorly understood. Lamina propria (LP) T helper 17 (Th17) cells participate in mucosal protection and are induced by commensal segmented filamentous bacteria (SFB). Here we show that MHCII-dependent antigen presentation of SFB antigens by intestinal dendritic cells (DCs) is crucial for Th17 cell induction. Expression of MHCII on CD11c(+) cells was necessary and sufficient for SFB-induced Th17 cell differentiation. Most SFB-induced Th17 cells recognized SFB in an MHCII-dependent manner. SFB primed and induced Th17 cells locally in the LP and Th17 cell induction occurred normally in mice lacking secondary lymphoid organs. The importance of other innate cells was unveiled by the finding that RORγt(+) innate lymphoid cells (ILCs) strongly inhibited SFB-independent Th17 cell differentiation in an MHCII-dependent manner. Our results outline the complex role of DCs and ILCs in the regulation of intestinal Th17 cell homeostasis.
    Immunity 03/2014; DOI:10.1016/j.immuni.2014.03.005 · 19.75 Impact Factor
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    ABSTRACT: High-affinity class-switched Abs and memory B cells are products of the germinal center (GC). The CD4(+) T cell help required for the development and maintenance of the GC is delivered by follicular Th cells (TFH), a CD4(+) Th cell subset characterized by expression of Bcl-6 and secretion of IL-21. The cellular interactions that mediate differentiation of TFH and GC B cells remain an important area of investigation. We previously showed that MHC class II (MHCII)-dependent dendritic cell Ag presentation is sufficient for the differentiation of a TFH intermediate (termed pre-TFH), characterized by Bcl-6 expression but lacking IL-21 secretion. In this article, we examine the contributions of MHCII Ag presentation by B cells to TFH differentiation and GC responses in several contexts. B cells alone do not efficiently prime naive CD4(+) T cells or induce TFH after protein immunization; however, during lymphocytic choriomeningitis virus infection, B cells induce TFH differentiation despite the lack of effector CD4(+) T cell generation. Still, MHCII(+) dendritic cells and B cells cooperate for optimal TFH and GC B cell differentiation in response to both model Ags and viral infection. This study highlights the roles for B cells in both CD4(+) T cell priming and TFH differentiation, and demonstrates that different APC subsets work in tandem to mediate the GC response.
    The Journal of Immunology 03/2014; 192(8). DOI:10.4049/jimmunol.1301284 · 5.36 Impact Factor
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    ABSTRACT: MHC class II (MHCII)-influenced CD4(+) T cell differentiation and function play critical roles in regulating the development of autoimmunity. The lack of hematopoietic MHCII causes autoimmune disease that leads to severe wasting in syngeneic recipients. Using murine models of bone marrow transplantation (BMT), we find that MHCII(-/-)→wild-type BMT developed disease, with defective development of innate memory phenotype (IMP, CD44(hi)/CD62L(lo)) CD4(+) T cells. Whereas conventional regulatory T cells are unable to suppress pathogenesis, IMP CD4(+) T cells, which include conventional regulatory T cells, can suppress pathogenesis in MHCII(-/-)→wild-type chimeras. The functional development of IMP CD4(+) T cells requires hematopoietic but not thymic MHCII. B cells and hematopoietic CD80/86 regulate the population size, whereas MHCII expression by dendritic cells is sufficient for IMP CD4(+) T cell functional development and prevention of pathogenesis. Furthermore, the absence of Tec kinase IL-2-inducible T cell kinase in MHCII(-/-) donors leads to preferential development of IMP CD4(+) T cells and partially prevents pathogenesis. We conclude that dendritic cells-MHCII and IL-2-inducible T cell kinase regulate the functional development of IMP CD4(+) T cells, which suppresses the development of autoimmune disorder in syngeneic BMTs.
    The Journal of Immunology 03/2014; 192(7). DOI:10.4049/jimmunol.1303176 · 5.36 Impact Factor
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    ABSTRACT: The innate and adaptive immune systems in the intestine cooperate to maintain the integrity of the intestinal barrier and to regulate the composition of the resident microbiota. However, little is known about the crosstalk between the innate and adaptive immune systems that contribute to this homeostasis. We find that CD4+ T cells regulate the number and function of barrier-protective innate lymphoid cells (ILCs), as well as production of antimicrobial peptides (AMPs), Reg3γ and Reg3β. RAG1-/- mice lacking T and B cells had elevated ILC numbers, interleukin-22 (IL-22) production, and AMP expression, which were corrected by replacement of CD4+ T cells. Major histocompatibility class II-/- (MHCII-/-) mice lacking CD4+ T cells also had increased ILCs, IL-22, and AMPs, suggesting that negative regulation by CD4+ T cells occurs at steady state. We utilized transfers and genetically modified mice to show that reduction of IL-22 is mediated by conventional CD4+ T cells and is T-cell receptor dependent. The IL-22-AMP axis responds to commensal bacteria; however, neither the bacterial repertoire nor the gross localization of commensal bacteria differed between MHCII+/- and MHCII-/- littermates. These data define a novel ability of CD4+ T cells to regulate intestinal IL-22-producing ILCs and AMPs.Mucosal Immunology advance online publication, 22 January 2014; doi:10.1038/mi.2013.121.
    Mucosal Immunology 01/2014; 7(5). DOI:10.1038/mi.2013.121 · 7.54 Impact Factor
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    ABSTRACT: The activation, differentiation, and subsequent effector functions of CD4 T cells depend on interactions with a multitude of MHC class II (MHCII)-expressing APCs. To evaluate the individual contribution of various APCs to CD4 T cell function, we have designed a new murine tool for selective in vivo expression of MHCII in subsets of APCs. Conditional expression of MHCII in B cells was achieved using a cre-loxP approach. After i.v. or s.c. priming, partial proliferation and activation of CD4 T cells was observed in mice expressing MHCII only by B cells. Restricting MHCII expression to B cells constrained secondary CD4 T cell responses in vivo, as demonstrated in a CD4 T cell-dependent model of autoimmunity, experimental autoimmune encephalomyelitis. These results highlight the limitations of B cell Ag presentation during initiation and propagation of CD4 T cell function in vivo using a novel system to study individual APCs by the conditional expression of MHCII.
    The Journal of Immunology 06/2013; 191(2). DOI:10.4049/jimmunol.1201598 · 5.36 Impact Factor
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    ABSTRACT: Effective major histocompatibility complex-II (MHC-II) antigen presentation from phagocytosed particles requires phagosome-intrinsic Toll-like receptor (TLR) signaling, but the molecular mechanisms underlying TLR delivery to phagosomes and how signaling regulates antigen presentation are incompletely understood. We show a requirement in dendritic cells (DCs) for adaptor protein-3 (AP-3) in efficient TLR recruitment to phagosomes and MHC-II presentation of antigens internalized by phagocytosis but not receptor-mediated endocytosis. DCs from AP-3-deficient pearl mice elicited impaired CD4(+) T cell activation and Th1 effector cell function to particulate antigen in vitro and to recombinant Listeria monocytogenes infection in vivo. Whereas phagolysosome maturation and peptide:MHC-II complex assembly proceeded normally in pearl DCs, peptide:MHC-II export to the cell surface was impeded. This correlated with reduced TLR4 recruitment and proinflammatory signaling from phagosomes by particulate TLR ligands. We propose that AP-3-dependent TLR delivery from endosomes to phagosomes and subsequent signaling mobilize peptide:MHC-II export from intracellular stores.
    Immunity 05/2012; 36(5):782-94. DOI:10.1016/j.immuni.2012.02.018 · 19.75 Impact Factor
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    Tom Li Stephen, Bridget S Wilson, Terri M Laufer
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    ABSTRACT: Mature peripheral T cells respond to foreign but not to self-antigens. During development in the thymus, deletion of high-affinity self-reactive immature thymocytes contributes to tolerance of mature T cells. However, double-positive thymocytes are positively selected to survive if they respond to self-peptide-MHC complexes; thus, there must be mechanisms to prevent overt reactivity to those same complexes in the periphery. "Developmental tuning" is the active process through which T-cell receptor (TCR)-associated signaling pathways of single-positive (SP) thymocytes are attenuated to respond appropriately to self-peptide-MHC complexes in the periphery. We previously showed that MHC class II expression in the thymic medulla was necessary to tune CD4(+) SP (CD4 SP) thymocytes. CD4 SP thymocytes from mice lacking medullary MHC class II expression had inappropriately enhanced proximal TCR signaling to low-affinity self-ligands that was associated with altered cellular distribution of the tyrosine kinase Lck. Now, we report that activation of both tuned and untuned CD4 SP thymocytes is Lck-dependent. Untuned CD4 SP cells contain a pool of Lck with increased basal phosphorylation that is not associated with the CD4 coreceptor. Phosphorylation of this pool of Lck decreases with tuning. Immunogold transmission electron microscopy of membrane sheets permitted direct visualization of Lck. In the absence of tuning, a significant proportion of Lck and the TCR subunit CD3ζ are expressed on the same protein island; this close association of Lck and the TCR probably explains the enhanced activation of untuned CD4 SP cells. Thus, changes in membrane topography during thymic maturation determine the set point for TCR responsiveness.
    Proceedings of the National Academy of Sciences 04/2012; 109(19):7415-20. DOI:10.1073/pnas.1119272109 · 9.81 Impact Factor
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    ABSTRACT: Lifelong antibody responses to vaccination require reorganization of lymphoid tissue and dynamic intercellular communication called the germinal center reaction. B lymphocytes undergo cellular polarization during antigen stimulation, acquisition, and presentation, which are critical steps for initiating humoral immunity. Here, we show that germinal center B lymphocytes asymmetrically segregate the transcriptional regulator Bcl6, the receptor for interleukin-21, and the ancestral polarity protein atypical protein kinase C to one side of the plane of division, generating unequal inheritance of fate-altering molecules by daughter cells. Germinal center B lymphocytes from mice with a defect in leukocyte adhesion fail to divide asymmetrically. These results suggest that motile cells lacking constitutive attachment can receive provisional polarity cues from the microenvironment to generate daughter cell diversity and self-renewal.
    Science 12/2011; 335(6066):342-4. DOI:10.1126/science.1213495 · 31.48 Impact Factor
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    ABSTRACT: The adaptor protein Src homology 2 domain-containing leukocyte-specific protein of 76 kDa (SLP-76) is central to the organization of intracellular signaling downstream of the T-cell receptor (TCR). Evaluation of its role in mature, primary T cells has been hampered by developmental defects that occur in the absence of WT SLP-76 protein in thymocytes. Here, we show that following tamoxifen-regulated conditional deletion of SLP-76, mature, antigen-inexperienced T cells maintain normal TCR surface expression but fail to transduce TCR-generated signals. Conditionally deficient T cells fail to proliferate in response to antigenic stimulation or a lymphopenic environment. Mice with induced deletion of SLP-76 are resistant to induction of the CD4+ T-cell-mediated autoimmune disease experimental autoimmune encephalomyelitis. Altogether, our findings demonstrate the critical role of SLP-76-mediated signaling in initiating T-cell-directed immune responses both in vitro and in vivo and highlight the ability to analyze signaling processes in mature T cells in the absence of developmental defects.
    European Journal of Immunology 07/2011; 41(7):2064-73. DOI:10.1002/eji.201040809 · 4.52 Impact Factor
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    ABSTRACT: Follicular helper T (T(FH)) cells are critical for germinal center (GC) formation. The processes that drive their generation and effector potential remain unclear. In this study, we define requirements for MHC class II APCs in murine T(FH) cell formation by either transiently ablating or restricting Ag presentation to dendritic cells (DCs). We find that cognate interactions with DCs are necessary and sufficient to prime CD4(+) T cells toward a CXCR5(+)ICOS(+)Bcl6(+) T(FH) cell intermediate. However, in the absence of additional APCs, these T(FH) cells fail to produce IL-21. Furthermore, in vitro priming of naive T cells by B cells engenders optimal production of IL-21, which induces a GC B cell transcriptional profile. These results support a multistep model for effector T(FH) cell priming and GC initiation, in which DCs are necessary and sufficient to induce a T(FH) cell intermediate that requires additional interactions with distinct APCs for full effector function.
    The Journal of Immunology 06/2011; 187(3):1091-5. DOI:10.4049/jimmunol.1100853 · 5.36 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2011; 127(2). DOI:10.1016/j.jaci.2010.12.375 · 11.25 Impact Factor
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    ABSTRACT: Experimental autoimmune encephalomyelitis (EAE), a model for the human disease multiple sclerosis (MS), is dependent upon the activation and effector functions of autoreactive CD4 T cells. Multiple interactions between CD4 T cells and major histocompatibility class II (MHCII)+ antigen presenting cells (APCs) must occur in both the periphery and central nervous system (CNS) to elicit autoimmunity. The identity of the MHCII+ APCs involved throughout this process remains in question. We investigated which APC in the periphery and CNS mediates disease using transgenic mice with MHCII expression restricted to dendritic cells (DCs). MHCII expression restricted to DCs results in normal susceptibility to peptide-mediated EAE. Indeed, radiation-sensitive bone marrow-derived DCs were sufficient for all APC functions during peptide-induced disease. However, DCs alone were inefficient at promoting disease after immunization with the myelin protein myelin oligodendrocyte glycoprotein (MOG), even in the presence of MHCII-deficient B cells. Consistent with a defect in disease induction following protein immunization, antigen presentation by DCs alone was incapable of mediating spontaneous optic neuritis. These results indicate that DCs are capable of perpetuating CNS-targeted autoimmunity when antigens are readily available, but other APCs are required to efficiently initiate pathogenic cognate CD4 T cell responses.
    Journal of Autoimmunity 02/2011; 36(1):56-64. DOI:10.1016/j.jaut.2010.10.006 · 7.02 Impact Factor
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    ABSTRACT: Ezrin/radixin/moesin (ERM) proteins are highly homologous proteins that function to link cargo molecules to the actin cytoskeleton. Ezrin and moesin are both expressed in mature lymphocytes, where they play overlapping roles in cell signaling and polarity, but their role in lymphoid development has not been explored. We characterized ERM protein expression in lymphoid tissues and analyzed the requirement for ezrin expression in lymphoid development. In wildtype mice, we found that most cells in the spleen and thymus express both ezrin and moesin, but little radixin. ERM protein expression in the thymus was differentially regulated, such that ezrin expression was highest in immature thymocytes and diminished during T cell development. In contrast, moesin expression was low in early thymocytes and upregulated during T cell development. Mice bearing a germline deletion of ezrin exhibited profound defects in the size and cellularity of the spleen and thymus, abnormal thymic architecture, diminished hematopoiesis, and increased proportions of granulocytic precursors. Further analysis using fetal liver chimeras and thymic transplants showed that ezrin expression is dispensable in hematopoietic and stromal lineages, and that most of the defects in lymphoid development in ezrin(-/-) mice likely arise as a consequence of nutritional stress. We conclude that despite high expression in lymphoid precursor cells, ezrin is dispensable for lymphoid development, most likely due to redundancy with moesin.
    PLoS ONE 08/2010; 5(8):e12404. DOI:10.1371/journal.pone.0012404 · 3.53 Impact Factor
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    Terri M Laufer
    Immunological Reviews 01/2010; 233(1):5-8. DOI:10.1111/j.0105-2896.2009.00869.x · 12.91 Impact Factor
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    ABSTRACT: Immature thymocytes that are positively selected based upon their response to self-peptide-MHC complexes develop into mature T cells that are not overtly reactive to those same complexes. Developmental tuning is the active process through which TCR-associated signaling pathways of single-positive thymocytes are attenuated to respond appropriately to the peptide-MHC molecules that will be encountered in the periphery. In this study, we explore the mechanisms that regulate the tuning of CD4(+) single-positive T cells to MHC class II encountered in the thymic medulla. Experiments with murine BM chimeras demonstrate that tuning can be mediated by MHC class II expressed by either thymic medullary epithelial cells or thymic dendritic cells. Tuning does not require the engagement of CD4 by MHC class II on stromal cells. Rather, it is mediated by interactions between MHC class II and the TCR. To understand the molecular changes that distinguish immature hyperactive T cells from tuned mature CD4(+) T cells, we compared their responses to TCR stimulation. The altered response of mature CD4 single-positive thymocytes is characterized by the inhibition of ERK activation by low-affinity self-ligands and increased expression of the inhibitory tyrosine phosphatase SHP-1. Thus, persistent TCR engagement by peptide-MHC class II on thymic medullary stroma inhibits reactivity to self-Ags and prevents autoreactivity in the mature repertoire.
    The Journal of Immunology 11/2009; 183(9):5554-62. DOI:10.4049/jimmunol.0901104 · 5.36 Impact Factor
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    ABSTRACT: In allergic airway inflammation, dendritic cells (DCs) are required for Th2 generation, recruitment, and activation in the respiratory tract. DCs have been shown to be necessary and sufficient for the induction of Th1 immune responses. In Th2 immunity and allergic airway inflammation, the ability of a DC to function as the sole APC has not been tested. We show that CD11c/A(beta)(b) mice with MHC class II expression restricted to CD11c-expressing DCs develop airway neutrophilia rather than allergic airway inflammation. Although CD11c/A(beta)(b) mice are capable of Th2 recruitment and activation in the lung, Th2 priming in CD11c/A(beta)(b) mice results in IFN-gamma production. Effective Th2 generation and allergic airway inflammation was achieved in CD11c/A(beta)(b) mice after treatment with anti-IFN-gamma. These studies show that DCs alone cannot drive the development of Th2 cells but require an additional MHC class II signal to stimulate effective Th2 immunity.
    The Journal of Immunology 09/2009; 183(3):1523-7. DOI:10.4049/jimmunol.0901349 · 5.36 Impact Factor
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    ABSTRACT: T helper type 2 (T(H)2)-mediated immune responses are induced after infection with multicellular parasites and can be triggered by a variety of allergens. The mechanisms of induction and the antigen-presenting cells involved in the activation of T(H)2 responses remain poorly defined, and the innate immune sensing pathways activated by parasites and allergens are largely unknown. Basophils are required for the in vivo induction of T(H)2 responses by protease allergens. Here we show that basophils also function as antigen-presenting cells. We show that although dendritic cells were dispensable for allergen-induced activation of T(H)2 responses in vitro and in vivo, antigen presentation by basophils was necessary and sufficient for this. Thus, basophils function as antigen-presenting cells for T(H)2 differentiation in response to protease allergens.
    Nature Immunology 08/2009; 10(7):713-20. DOI:10.1038/ni.1738 · 24.97 Impact Factor

Publication Stats

3k Citations
631.34 Total Impact Points

Institutions

  • 2001–2015
    • University of Pennsylvania
      • • Department of Medicine
      • • Division of Rheumatology
      Filadelfia, Pennsylvania, United States
  • 2008–2014
    • William Penn University
      Worcester, Massachusetts, United States
  • 2009
    • Minneapolis Veterans Affairs Hospital
      Minneapolis, Minnesota, United States
  • 2007
    • Hospital of the University of Pennsylvania
      • Department of Neurology
      Filadelfia, Pennsylvania, United States
  • 1997–1999
    • Harvard Medical School
      • Department of Medicine
      Boston, MA, United States
  • 1996–1999
    • Harvard University
      • Department of Immunology and Infectious Diseases
      Cambridge, Massachusetts, United States
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 1993–1998
    • Massachusetts Department of Public Health
      Boston, Massachusetts, United States