Charles A. Janeway

Howard Hughes Medical Institute, Ashburn, Virginia, United States

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Publications (255)2797.12 Total impact

  • Immunological Reviews 04/2006; 101(1):39 - 80. DOI:10.1111/j.1600-065X.1988.tb00732.x · 10.12 Impact Factor
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    ABSTRACT: Our studies, and those of several other laboratories, appear to us to support a co-receptor function for CD4. While this does not deny the possible accessory molecule function of these interesting cell surface proteins, it is our belief that their role in T-cell activation can be understood more readily in terms of their functioning as part of the TCR antigen recognition and signal transduction apparatus than as passive accessory molecules that bind class II MHC molecules and play a role mainly in strengthening intercellular interactions. Our evidence supporting this comes from several different lines on experimentation: Our data show that steric interference between anti-TCR and anti-CD4 antibodies can inhibit T-cell acivation, that anti-TCR antibodies that induce CD4 association with the TCR are at least 100 times more effective in activating T cells than are antibodies that do not trigger this association, and that direct cross-linking of CD4 and the TCR greatly potentiates signalling. These studies suggest that CD4 binds in a highly specific fashion to the TCR and to class II MHC molecules. If this is so, then the TCR and class II MHC must bind to one another in a highly precise fashion during antigen recognition also. This, in turn, has interesting implications for the relative roles of different parts of the TCR in recognizing different parts of the complex antigen:self class II MHC ligand. The docking of CD4 on the TCR is normally induced by the binding of both molecules to class II MHC. Class I MHC could not serve this function, since CD4 does not bind effectively to class I MHC molecules. Since the co-localization of CD4 with the TCR potentiates signalling by 100-fold, that is, since 100-fold less ligand is required to get activation of a given T cell when CD4 docking occurs than when it is absent, it is easy to understand the very strong association of CD4 expression and class II MHC restricted antigen recognition. When the ligand is allogenic class II MHC, then it is possible that the ligand density is far higher, and it is in these cases that one most readily observes CD8 T cells responding to class II MHC, and CD4 T cells responding to class I MHC. This new construction of the role of CD4 has important implications for thymic ontogeny as well. It appears that positive selection of self MHC restricted T cells occurs during the CD4, CD8 double-positive stage in T-cell development, and leads to the repressed expression of one of these two molecules (Janeway 1988). When the TCR is specific for class II MHC, CD4 serves as the co-receptor during positive selection and CD8 expression is repressed. The opposite is observed when the TCR is class I MHC restricted. Specific self MHC is required for these effects. This further suggests that, at least at this stage of development, signalling via CD4:TCR complexes is distinctive from signalling via CD8:TCR complexes, as shown by the different outcomes of these two events. Whether these putatively distinct signals also induce the functional distinctions seen in CD4 and CD8 T cells is not yet known.
    Immunological Reviews 04/2006; 109(1):77 - 92. DOI:10.1111/j.1600-065X.1989.tb00020.x · 10.12 Impact Factor
  • Charles A. Janeway ·

    Immunological Reviews 04/2006; 131(1):189 - 200. DOI:10.1111/j.1600-065X.1993.tb01536.x · 10.12 Impact Factor
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    Margaret S Bynoe · Christophe Viret · Richard A Flavell · Charles A Janeway ·
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    ABSTRACT: Epicutaneous immunization of T cell receptor (TCR) transgenic (Tg) mice whose CD4(+) T cells are specific for the Ac1-11 fragment of myelin basic protein (MBP) with Ac1-11 elicits T cells with dominant suppressor/regulatory activity that confers protection against Ac1-11-induced experimental autoimmune encephalomyelitis. We now report that such disease-resistant MBP TCR Tg mice also harbor a sizeable fraction of peripheral CD4(+) T cells lacking surface expression of the Tg TCR beta chain and expressing diverse, endogenously rearranged TCR beta chains. Ex vivo incubation at physiological temperature caused the loss of neo-beta-chain expression and reversion to the MBP alphabeta TCR(+) phenotype. The presence of recombination activating gene 1 and 2 proteins in CD4(+) T cells with revised TCRs was consistent with effective V(D)J recombination activity. The emergence of these cells did not depend on the thymic compartment. We conclude that in mice epicutaneously immunized with an autoantigen, peripheral specific T cells are susceptible to multiple mechanisms of tolerance.
    Proceedings of the National Academy of Sciences 03/2005; 102(8):2898-903. DOI:10.1073/pnas.0409880102 · 9.67 Impact Factor
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    ABSTRACT: Serine proteases play vital roles in several biological processes such as development and immunity. We have characterized Graal, a large multi-domain serine protease from Drosophila. Graal is spliced in at least three transcripts that are present throughout development. The domains found in Graal proteins are: chitin-binding domains (CBD), scavenger receptor cysteine-rich (SRCR) domains, low density lipoprotein receptor cysteine-rich (LDLR-CR) domains, histidine and proline-rich domains, a NGGYQPP-repeat domain and a serine protease domain. The last 2370 nucleotides of these RNAs are identical and encode a His-rich domain, two SRCR domains, two LDLR-CR domains and a protease domain. The transcription of graal is upregulated after fungal or bacterial infection. Analysis of the Iso1 (y;cn,sp,bw) strain shows that graal transcription is impaired in this fly line due to the insertion of a retrotransposon in the sixth exon. However, no phenotype could be observed consecutive to the absence of graal full length transcripts, particularly in the context of an immune challenge.
    Insect Biochemistry and Molecular Biology 11/2004; 34(10):1025-35. DOI:10.1016/j.ibmb.2003.09.009 · 3.45 Impact Factor
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    ABSTRACT: B-cells are important in the development of type 1 diabetes, but their role is not completely defined. Although B-cells produce autoantibodies, these are not thought to be pathogenic; however, their antigen-presenting function is postulated to be critical. To examine the relative importance of these functions of B-cells, we have generated nonobese diabetic (NOD) B-cell-deficient mice that express a transgene encoding a mutant heavy chain immunoglobulin transgene on the cell surface but cannot secrete immunoglobulins (mIgs). This allowed us to dissect the importance of the relative roles of antigen presentation, dissociated from antibody production. We found that the expression of the mIg transgene increased insulitis and the incidence of diabetes compared with transgene-negative NOD B-cell-deficient mice, indicating that the ability to produce antibodies is not necessary for B-cells to have some effect on the development of diabetes. However, diabetes was not restored to the level seen in normal NOD mice. This may relate to reduced ability to activate an islet-specific T-cell repertoire, presumably due to the reduced islet-specific B-cell repertoire. Our results implicate a specific antigen-presenting function for B-cells.
    Diabetes 11/2004; 53(10):2581-7. DOI:10.2337/diabetes.53.10.2581 · 8.10 Impact Factor
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    Margaret S Bynoe · J Tori Evans · Christophe Viret · Charles A Janeway ·
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    ABSTRACT: Information on how suppressor/regulatory T cells can be generated directly in vivo and prevent autoimmunity remains fragmentary. We show here that epicutaneous immunization (ECi) with the immunodominant peptide of myelin basic protein (MBP), Ac1-11, protects mice that are transgenic for an Ac1-11-specific T cell receptor against both the induced and spontaneous forms of experimental allergic encephalomyelitis (EAE). This protection was antigen specific and antigen dose dependent, and was mediated by CD4(+)/CD25(-) T cells whose suppressive activity required cell-cell contact and could transfer protection to naive recipients. These ECi-induced suppressor T cells controlled naive MBP-specific CD4 T cells by inhibiting both their activation and their capacity to secrete IFN-gamma. There was no CD4 T cell infiltration in the brain of protected mice. Finally, ECi with autoantigenic peptides protected two nontransgenic models from relapsing-remitting EAE in an antigen-specific and antigen dose-dependent manner.
    Immunity 10/2003; 19(3):317-28. DOI:10.1016/S1074-7613(03)00239-5 · 21.56 Impact Factor
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    Christophe Viret · Xin He · Charles A Janeway ·
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    ABSTRACT: Thymocytes bearing the E alpha 52-68/I-A(b) complex-specific 1H3.1 alpha beta T cell antigen receptor are positively selected in Ab-Ep [Ab-Ep transgenic, invariant chain (Ii)(-/-), I-A beta(b-/-)] mice, where I-A(b) molecules present only E alpha 52-68. Although Ii reintroduction led to deletion, I-A beta(b) reintroduction disrupted positive selection. T cell antigen receptor transgenic Ab-Ep I-A beta(b+) mice had a large thymus with an increased absolute number of CD4(+)CD8(+) cells and no overt signs of deletion. Unlike Ab-Ep Ii(+) antigen-presenting cells, Ab-Ep I-A beta(b+) antigen-presenting cells did not activate 1H3.1 T cells. However, their capacity to present E alpha 52-68 was intact. Thus, positive selection of 1H3.1 thymocytes on the tight compact E alpha 52-68/I-A(b) complex is neutralized by the corecognition of loose compact self-peptide/I-A(b) conformers that do not interfere with the cognate activation of mature 1H3.1 T cells. The data support the notion that the integration of distinct signals generated by the simultaneous recognition of multiple self-peptide/MHC complexes directs intrathymic selection of T cells.
    Proceedings of the National Academy of Sciences 05/2003; 100(9):5354-9. DOI:10.1073/pnas.0831129100 · 9.67 Impact Factor
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    ABSTRACT: The L51S mutation in the D10.G4.1 TCR alpha-chain reduces the affinity of the TCR to its ligand by affecting the interactions among the TCR, the beta-chain of I-A(k), and the bound peptide. We show that this mutation drives the generation of a pool of memory CD44(high)CD62L(neg)CD45RB(neg) CD4 TCR transgenic T cells. Their activation threshold is low, such that they proliferate in response to lower concentrations of agonist peptides than naive L51S CD4 T cells. Unlike effector memory CD4 T cells, however, they lack immediate effector function in response to TCR stimulation. These cells express IL-2R alpha only after culture with specific peptide. Although they can be recovered from lymph nodes, the majority lack the expression of the lymph node homing receptor CCR7. When these cells receive a second TCR stimulation in vitro, they differentiate into potent Th2-like effector cells, producing high levels of IL-4 at doses of agonist peptide too low to stimulate cytokine release from similarly differentiated naive L51S CD4 T cells. Having these properties, the L51S TCR transgenic memory CD4 T cells cannot be classified as either strict central memory or effector memory, but, rather, as a pool of memory T cells containing effector memory precursors.
    The Journal of Immunology 04/2003; 170(6):2940-8. DOI:10.4049/jimmunol.170.6.2940 · 4.92 Impact Factor
  • Gobardhan Das · Charles A Janeway ·
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    ABSTRACT: Intestinal intra-epithelial lymphocytes (iIELs) are a major lymphocyte population, reside in close proximity to the intestinal lumen and are conserved throughout vertebrate evolution. iIELs consist of several unique T-cell phenotypes and express both non-rearranged innate immune receptors and rearranged adaptive immune receptors. The ligands for the innate immune receptors on iIELs, such as NKG2D (natural killer-cell receptor), often bind to non-classical MHC class I molecules, such as the human MHC class I-related molecules MICA or MICB. These ligands costimulate T-cell receptor (TCR)-mediated signaling. In most cases, the MHC molecules that bind to the TCR are still unknown. However, recent efforts to understand the MHC molecules that are involved in the development of and antigen recognition by iIELs have revealed several important results. Here, we focus systematically on recent developments in innate immunity and in TCR recognition of different subtypes of iIELs by various MHC molecules.
    Trends in Immunology 03/2003; 24(2):88-93. DOI:10.1016/S1471-4906(02)00036-4 · 10.40 Impact Factor
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    Christophe Viret · Charles A Janeway ·
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    ABSTRACT: In the presence of the I-Ealpha protein, transgenic (Tg) mice expressing the 1H3.1 alphabeta TCR that is specific for the Ealpha52-68:I-A(b) complex display drastic intrathymic deletion. Although peripheral T cells from these mice remained unresponsive to the Ealpha52-68:I-A(b) complex, they contained a subpopulation able to specifically react to this complex in the presence of exogenous IL-2, indicating that some 1H3.1 alphabeta TCR Tg T cells have escaped clonal deletion and efficiently populated the periphery. IL-2-dependent, Ealpha52-68:I-A(b) complex-responsive T cells were CD4-CD8- and expressed the 1H3.1 alphabeta TCR. Such T cells could develop intrathymically, did not show sign of regulatory/suppressor activity, displayed a typical naive phenotype, and seemed to persist in vivo over time. CD4-CD8- TCR Tg T cells were also detected when the surface density of the deleting ligand was increased on MHC class II+ cells. In addition, the development of CD4-CD8- 1H3.1 alphabeta TCR Tg T cells could be supported by I-A(b) molecules. These observations indicate that CD4 surface expression neither specifies, nor is required for, the thymic export of mature thymocytes expressing a MHC class II-restricted alphabeta TCR. The data also show that, although the avidity of the interaction involved in intrathymic deletion is significantly lower than that involved in mature T cell activation, its range can be large enough to be influenced by the presence or absence of coreceptors. Finally, the margin created by the absence of CD4 coreceptor was substantial because it could accommodate various amounts of the deleting ligand on thymic stromal cells.
    The Journal of Immunology 02/2003; 170(1):201-9. DOI:10.4049/jimmunol.170.1.201 · 4.92 Impact Factor
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    ABSTRACT: Blood cells play a crucial role in both morphogenetic and immunological processes in Drosophila, yet the factors regulating their proliferation remain largely unknown. In order to address this question, we raised antibodies against a tumorous blood cell line and identified an antigenic determinant that marks the surface of prohemocytes and also circulating plasmatocytes in larvae. This antigen was identified as a Drosophila homolog of the mammalian receptor for platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF). The Drosophila receptor controls cell proliferation in vitro. By overexpressing in vivo one of its putative ligands, PVF2, we induced a dramatic increase in circulating hemocytes. These results identify the PDGF/VEGF receptor homolog and one of its ligands as important players in Drosophila hematopoiesis.
    EMBO Reports 01/2003; 3(12):1195-200. DOI:10.1093/embo-reports/kvf242 · 9.06 Impact Factor
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    Hilda Holcombe · Ira Mellman · Charles A Janeway · Kim Bottomly · Bonnie N Dittel ·
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    ABSTRACT: Immunosuppressive agents are commonly used in the prevention of graft rejection following transplantation and in the treatment of autoimmunity. In this study, we examined the immunosuppressive mechanism of the drug 15-deoxyspergualin (DSG), which has shown efficacy in the enhancement of graft survival and in the treatment of autoimmunity. Using a murine model of chronic relapsing and remitting experimental autoimmune encephalomyelitis, we were able to demonstrate that DSG both delayed and reduced the severity of experimental autoimmune encephalomyelitis. Subsequent in vitro studies to examine the mechanism of immune suppression showed that DSG was not able to inhibit early activation of naive CD4 T cells, but DSG did effectively inhibit the growth of naive CD4 T cells after activation. An analysis of cell proliferation and cell cycle showed that DSG treatment led to a block in cell cycle progression 2-3 days following Ag stimulation. In addition, DSG treatment inhibited the production of IFN-gamma by Th1 effector T cells. These studies suggest that CD4 T cells are a predominant target for DSG and the immunosuppressive effects of the drug may result from reduced CD4 T cell expansion and decreased polarization into IFN-gamma-secreting Th1 effector T cells in the induction of certain autoimmune disorders.
    The Journal of Immunology 12/2002; 169(9):4982-9. DOI:10.4049/jimmunol.169.9.4982 · 4.92 Impact Factor
  • Xin He · Christophe Viret · Charles A Janeway ·
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    ABSTRACT: Detailed sequence analysis of the companion alpha chains in several T-cell receptor (TCR) beta chain transgenic mice have shown that the mature alpha chain repertoires of CD4+ T cells are biased toward the parental TCR alpha chain sequences. These studies further indicate that it is self-peptide-self-MHC recognition during positive intrathymic selection that biases the structure of the mature TCR alpha chain repertoire. To further establish the causative relationship, it is important to examine whether such a bias can be abolished when positive selection is absent. The human collagen IV-I-A(s) complex-specific KB TCR cannot be positively selected on the self-peptide-self-MHC complexes present in the I-A(s) strain. Therefore, the KB TCR beta chain transgenic mice offer a unique opportunity for addressing this issue.
    Trends in Immunology 11/2002; 23(10):467-9. DOI:10.1016/S1471-4906(02)02306-2 · 10.40 Impact Factor
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    Derek B Sant'Angelo · Eve Robinson · Charles A Janeway · Lisa K Denzin ·
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    ABSTRACT: CD4 T cells recognize peptides bound to major histocompatibility complex (MHC) class II molecules. Most MHC class II molecules have four binding pockets occupied by amino acids 1, 4, 6, and 9 of the minimal peptide epitope, while the residues at positions 2, 3, 5, 7, and 8 are available to interact with the T cell receptor (TCR). In addition MHC class II bound peptides have flanking residues situated outside of this peptide core. Here we demonstrate that the flanking residues of the conalbumin peptide bound to I-A(k) have no effect on recognition by the D10 TCR. To study the role of peptide flanks for recognition by a second TCR, we determined the MHC and TCR contacting amino acids of the I-A(b) bound Ealpha peptide. The Ealpha peptide is shown to bind I-A(b) using four alanines as anchor residues. TCR recognition of Ealpha peptides with altered flanking residues again suggested that, in general, no specific interactions occurred with the peptide flanks. However, using an HLA-DM-mediated technique to measure peptide binding to MHC class II molecules, we found that the peptide flanking residues contribute substantially to MHC binding.
    European Journal of Immunology 09/2002; 32(9):2510-20. DOI:10.1002/1521-4141(200209)32:9<2510::AID-IMMU2510>3.0.CO;2-Q · 4.03 Impact Factor
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    ABSTRACT: Toll-like receptors (TLRs) detect microorganisms and protect multicellular organisms from infection. TLRs transduce their signals through MyD88 and the serine/threonine kinase IRAK. The IRAK family consists of two active kinases, IRAK and IRAK-4, and two inactive kinases, IRAK-2 and IRAK-M. IRAK-M expression is restricted to monocytes/macrophages, whereas other IRAKs are ubiquitous. We show here that IRAK-M is induced upon TLR stimulation and negatively regulates TLR signaling. IRAK-M prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. Endotoxin tolerance, a protection mechanism against endotoxin shock, was significantly reduced in IRAK-M(-/-) cells. Thus, IRAK-M regulates TLR signaling and innate immune homeostasis.
    Cell 08/2002; 110(2):191-202. DOI:10.1016/S0092-8674(02)00827-9 · 32.24 Impact Factor
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    ABSTRACT: To analyse the effects of TGF-beta in insulin dependent diabetes mellitus (IDDM), we have developed non-obese diabetic (NOD) transgenic mice expressing TGF-beta under the control of the rat insulin II promoter. Pancreata of TGF-beta transgenic mice were roughly one twentieth of the size of pancreata of wild-type NOD mice and showed small clusters of micro-islets rather than normal adult islets. However, these islets produced sufficient levels of insulin to maintain normal glucose levels and mice were protected from the diabetes, which developed in their negative littermates. A massive fibrosis was seen in the transgenic pancreata that was accompanied with infiltration of mononuclear cells that decreased with age. Interestingly, these mice showed normal anti-islet immune response in their spleens and remained susceptible to adoptive transfer of IDDM by mature cloned CD8 effector cells. TUNEL assays revealed increased apoptosis of invading cells when compared to non-transgenic NOD mice. Taken together, these results suggest that TGF-beta protects islets by a local event.
    Journal of Autoimmunity 08/2002; 19(1-2):9-22. DOI:10.1006/jaut.2002.0599 · 8.41 Impact Factor
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    Derek B Sant'Angelo · Charles A Janeway ·
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    ABSTRACT: We have analyzed the patterns of positive and negative selection of thymocytes expressing the T cell antigen receptor (TCR) from the D10.G4.1 T cell clone. This TCR confers reactivity to several non-self MHC class II alleles with a remarkably broad range of avidities. Therefore, negative selection can be studied when induced by high-, intermediate-, or low-avidity interactions with endogenous peptide-MHC complexes, all within the same TCR transgenic system. These data directly demonstrate that MHC class II-peptide ligands that fail to activate mature T cells can promote negative selection of immature thymocytes. Additionally, we show that negative selection of thymocytes can occur at two distinct "time points" during development depending on the avidity of the TCR for the MHC-peptide complex. Finally, we show that the self-peptide repertoire plays a significant role in selection because alteration of the self-peptide repertoire by disruption of the H2-Ma gene drastically alters selection of D10 TCR-expressing thymocytes.
    Proceedings of the National Academy of Sciences 06/2002; 99(10):6931-6. DOI:10.1073/pnas.102182499 · 9.67 Impact Factor
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    ABSTRACT: The recognition of MHC-peptide complexes by T cells is governed by structural considerations that are determined by the sequences of the individual components and their interaction with each other. We have studied the function of a highly diabetogenic CD8 T cell clone that is specific for insulin B15-23:H-2K(d). We have then related this to modeled MHC-peptide structures. The native peptide binds poorly to H-2K(d), because of the small glycine residue at peptide position p9 that is incapable of productive interactions with the hydrophobic residues of pocket F. In addition, electrostatic repulsions between the peptide glutamate residue at position 7 and 152D of the MHC molecule heavy chain contribute to the poor binding. However, B chain peptide 15-23 bound to K(d) shows excellent T cell stimulation and the induction of CD8 cytotoxic T cells. Peptide substitution has also shown that p6G is likely to be a T cell antigen receptor interaction site. Our studies have shown that the predictions seen in the models correlate closely with the observed effects in functional assays and provide insight into how this peptide, which would not be predicted to stimulate these cells on H-2K(d) binding studies alone, could activate such highly pathogenic T cells.
    Proceedings of the National Academy of Sciences 05/2002; 99(8):5551-6. DOI:10.1073/pnas.072037299 · 9.67 Impact Factor
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    Ruslan Medzhitov · Charles A Janeway ·
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    ABSTRACT: The innate immune system evolved several strategies of self/nonself discrimination that are based on the recognition of molecular patterns demarcating infectious nonself, as well as normal and abnormal self. These patterns are deciphered by receptors that either induce or inhibit an immune response, depending on the meaning of these signals.
    Science 05/2002; 296(5566):298-300. DOI:10.1126/science.1068883 · 33.61 Impact Factor

Publication Stats

29k Citations
2,797.12 Total Impact Points


  • 1983-2006
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1980-2004
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
  • 1978-2000
    • Yale University
      • • Department of Immunobiology
      • • School of Medicine
      New Haven, Connecticut, United States
  • 1996
    • University of New Haven
      New Haven, Connecticut, United States
    • University of Toledo
      • Department of Medicinal and Biological Chemistry
      Toledo, OH, United States
  • 1994
    • Tokyo Junshin Women's College
      Edo, Tōkyō, Japan
  • 1993
    • Massachusetts Institute of Technology
      • Department of Biology
      Cambridge, Massachusetts, United States
  • 1982
    • Stanford University
      Stanford, California, United States
  • 1977-1979
    • Uppsala University
      Uppsala, Uppsala, Sweden
  • 1976
    • Stanford Medicine
      • Department of Genetics
      Stanford, California, United States
    • National Institutes of Health
      • Laboratory of Immunology
      Maryland, United States
  • 1975-1976
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Parasitic Diseases (LPD)
      Maryland, United States