Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 15

Publication Record

Connections

Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells.
Ooi JD, Petersen J, Tan YH, Huynh M, Willett ZJ, Ramarathinam SH, Eggenhuizen PJ, Loh KL, Watson KA, Gan PY, Alikhan MA, Dudek NL, Handel A, Hudson BG, Fugger L, Power DA, Holt SG, Coates PT, Gregersen JW, Purcell AW, Holdsworth SR, La Gruta NL, Reid HH, Rossjohn J, Kitching AR
(2017) Nature 545: 243-247
MeSH Terms: Animals, Anti-Glomerular Basement Membrane Disease, Autoimmunity, Base Sequence, CD4-Positive T-Lymphocytes, Collagen Type IV, Cytokines, Female, Forkhead Transcription Factors, HLA-DR Serological Subtypes, HLA-DR1 Antigen, Humans, Immunodominant Epitopes, Male, Mice, Mice, Transgenic, Models, Molecular, T-Lymphocytes, Regulatory
Show Abstract · Added June 2, 2017
Susceptibility and protection against human autoimmune diseases, including type I diabetes, multiple sclerosis, and Goodpasture disease, is associated with particular human leukocyte antigen (HLA) alleles. However, the mechanisms underpinning such HLA-mediated effects on self-tolerance remain unclear. Here we investigate the molecular mechanism of Goodpasture disease, an HLA-linked autoimmune renal disorder characterized by an immunodominant CD4 T-cell self-epitope derived from the α3 chain of type IV collagen (α3). While HLA-DR15 confers a markedly increased disease risk, the protective HLA-DR1 allele is dominantly protective in trans with HLA-DR15 (ref. 2). We show that autoreactive α3-specific T cells expand in patients with Goodpasture disease and, in α3-immunized HLA-DR15 transgenic mice, α3-specific T cells infiltrate the kidney and mice develop Goodpasture disease. HLA-DR15 and HLA-DR1 exhibit distinct peptide repertoires and binding preferences and present the α3 epitope in different binding registers. HLA-DR15-α3 tetramer T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (T) that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-α3 tetramer T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4Foxp3 regulatory T cells (T cells) expressing tolerogenic cytokines. HLA-DR1-induced T cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15 and HLA-DR1 healthy human donors display altered α3-specific T-cell antigen receptor usage, HLA-DR15-α3 tetramer Foxp3 T and HLA-DR1-α3 tetramer Foxp3CD25CD127 T dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded α3-specific CD4 T-cell repertoire. Accordingly, we provide a mechanistic basis for the dominantly protective effect of HLA in autoimmune disease, whereby HLA polymorphism shapes the relative abundance of self-epitope specific T cells that leads to protection or causation of autoimmunity.
1 Communities
1 Members
0 Resources
18 MeSH Terms
Human Antibodies that Recognize Novel Immunodominant Quaternary Epitopes on the HIV-1 Env Protein.
Hicar MD, Chen X, Sulli C, Barnes T, Goodman J, Sojar H, Briney B, Willis J, Chukwuma VU, Kalams SA, Doranz BJ, Spearman P, Crowe JE
(2016) PLoS One 11: e0158861
MeSH Terms: Antibodies, Monoclonal, Antibodies, Neutralizing, B-Lymphocytes, HIV Antibodies, HIV Envelope Protein gp41, HIV Infections, HIV-1, Humans, Immunodominant Epitopes, Protein Domains, Recombinant Proteins, env Gene Products, Human Immunodeficiency Virus
Show Abstract · Added April 13, 2017
Numerous broadly neutralizing antibodies (Abs) target epitopes that are formed or enhanced during mature HIV envelope formation (i.e. quaternary epitopes). Generally, it is thought that Env epitopes that induce broadly neutralizing Abs are difficult to access and poorly immunogenic because of the characteristic oligomerization, conformational flexibility, sequence diversity and extensive glycosylation of Env protein. To enhance for isolation of quaternary epitope-targeting Abs (QtAbs), we previously used HIV virus-like particles (VLPs) to bind B cells from long-term non-progressor subjects to identify a panel of monoclonal Abs. When expressed as recombinant full-length Abs, a subset of these novel Abs exhibited the binding profiles of QtAbs, as they either failed to bind to monomeric Env protein or showed much higher affinity for Env trimers and VLPs. These QtAbs represented a significant proportion of the B-cell response identified with VLPs. The Ab genes of these clones were highly mutated, but they did not neutralize common HIV strains. We sought to further define the epitopes targeted by these QtAbs. Competition-binding and mapping studies revealed these Abs targeted four separate epitopes; they also failed to compete for binding by Abs to known major neutralizing epitopes. Detailed epitope mapping studies revealed that two of the four epitopes were located in the gp41 subunit of Env. These QtAbs bound pre-fusion forms of antigen and showed differential binding kinetics depending on whether oligomers were produced as recombinant gp140 trimers or as full-length Env incorporated into VLPs. Antigenic regions within gp41 present unexpectedly diverse structural epitopes, including these QtAb epitopes, which may be targeted by the naturally occurring Ab response to HIV infection.
0 Communities
1 Members
0 Resources
12 MeSH Terms
Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody.
Kong R, Xu K, Zhou T, Acharya P, Lemmin T, Liu K, Ozorowski G, Soto C, Taft JD, Bailer RT, Cale EM, Chen L, Choi CW, Chuang GY, Doria-Rose NA, Druz A, Georgiev IS, Gorman J, Huang J, Joyce MG, Louder MK, Ma X, McKee K, O'Dell S, Pancera M, Yang Y, Blanchard SC, Mothes W, Burton DR, Koff WC, Connors M, Ward AB, Kwong PD, Mascola JR
(2016) Science 352: 828-33
MeSH Terms: AIDS Vaccines, Amino Acid Sequence, Antibodies, Neutralizing, Antibodies, Viral, B-Lymphocytes, Crystallography, X-Ray, HIV Envelope Protein gp120, HIV Envelope Protein gp41, HIV-1, Humans, Hydrophobic and Hydrophilic Interactions, Immunodominant Epitopes, Molecular Sequence Data, Peptides, Protein Conformation, Viral Fusion Proteins, Virus Internalization
Show Abstract · Added May 3, 2017
The HIV-1 fusion peptide, comprising 15 to 20 hydrophobic residues at the N terminus of the Env-gp41 subunit, is a critical component of the virus-cell entry machinery. Here, we report the identification of a neutralizing antibody, N123-VRC34.01, which targets the fusion peptide and blocks viral entry by inhibiting conformational changes in gp120 and gp41 subunits of Env required for entry. Crystal structures of N123-VRC34.01 liganded to the fusion peptide, and to the full Env trimer, revealed an epitope consisting of the N-terminal eight residues of the gp41 fusion peptide and glycan N88 of gp120, and molecular dynamics showed that the N-terminal portion of the fusion peptide can be solvent-exposed. These results reveal the fusion peptide to be a neutralizing antibody epitope and thus a target for vaccine design.
Copyright © 2016, American Association for the Advancement of Science.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Association of VH4-59 Antibody Variable Gene Usage with Recognition of an Immunodominant Epitope on the HIV-1 Gag Protein.
Chukwuma VU, Hicar MD, Chen X, Nicholas KJ, Joyner A, Kalams SA, Landucci G, Forthal DN, Spearman PW, Crowe JE
(2015) PLoS One 10: e0133509
MeSH Terms: Amino Acid Sequence, Antibodies, Monoclonal, B-Lymphocytes, Gene Products, gag, Genes, Immunoglobulin, HIV Antibodies, HIV Infections, HIV-1, Humans, Immunodominant Epitopes, Molecular Sequence Data, Neutralization Tests, T-Lymphocytes, Virion
Show Abstract · Added January 26, 2016
The human antibody response against HIV-1 infection recognizes diverse antigenic subunits of the virion, and includes a high level of antibodies to the Gag protein. We report here the isolation and characterization of a subset of Gag-specific human monoclonal antibodies (mAbs) that were prevalent in the antibody repertoire of an HIV-infected individual. Several lineages of Gag-specifc mAbs were encoded by a single antibody heavy chain variable region, VH4-59, and a representative antibody from this group designated mAb 3E4 recognized a linear epitope on the globular head of the p17 subunit of Gag. We found no evidence that mAb 3E4 exhibited any function in laboratory studies aimed at elucidating the immunologic activity, including assays for neutralization, Ab-dependent cell-mediated virus inhibition, or enhanced T cell reactivity caused by Gag-3E4 complexes. The findings suggest this immunodominant epitope in Gag protein, which is associated with VH4-59 germline gene usage, may induce a high level of B cells that encode binding but non-functional antibodies that occupy significant repertoire space following HIV infection. The studies define an additional specific molecular mechanism in the immune distraction activity of the HIV virion.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Discovering naturally processed antigenic determinants that confer protective T cell immunity.
Gilchuk P, Spencer CT, Conant SB, Hill T, Gray JJ, Niu X, Zheng M, Erickson JJ, Boyd KL, McAfee KJ, Oseroff C, Hadrup SR, Bennink JR, Hildebrand W, Edwards KM, Crowe JE, Williams JV, Buus S, Sette A, Schumacher TN, Link AJ, Joyce S
(2013) J Clin Invest 123: 1976-87
MeSH Terms: Animals, Antigen Presentation, Antigens, CD8-Positive T-Lymphocytes, Epitopes, Epitopes, T-Lymphocyte, HeLa Cells, Histocompatibility Antigens Class I, Humans, Immunodominant Epitopes, Mass Spectrometry, Mice, Mice, Transgenic, Peptides, Phenotype, T-Lymphocytes, Vaccinia virus
Show Abstract · Added March 20, 2014
CD8+ T cells (TCD8) confer protective immunity against many infectious diseases, suggesting that microbial TCD8 determinants are promising vaccine targets. Nevertheless, current T cell antigen identification approaches do not discern which epitopes drive protective immunity during active infection - information that is critical for the rational design of TCD8-targeted vaccines. We employed a proteomics-based approach for large-scale discovery of naturally processed determinants derived from a complex pathogen, vaccinia virus (VACV), that are presented by the most frequent representatives of four major HLA class I supertypes. Immunologic characterization revealed that many previously unidentified VACV determinants were recognized by smallpox-vaccinated human peripheral blood cells in a variegated manner. Many such determinants were recognized by HLA class I-transgenic mouse immune TCD8 too and elicited protective TCD8 immunity against lethal intranasal VACV infection. Notably, efficient processing and stable presentation of immune determinants as well as the availability of naive TCD8 precursors were sufficient to drive a multifunctional, protective TCD8 response. Our approach uses fundamental insights into T cell epitope processing and presentation to define targets of protective TCD8 immunity within human pathogens that have complex proteomes, suggesting that this approach has general applicability in vaccine sciences.
1 Communities
5 Members
0 Resources
17 MeSH Terms
Enhancement of the CD8+ T cell response to a subdominant epitope of respiratory syncytial virus by deletion of an immunodominant epitope.
Mok H, Lee S, Wright DW, Crowe JE
(2008) Vaccine 26: 4775-82
MeSH Terms: Amino Acid Substitution, Animals, CD8-Positive T-Lymphocytes, Epitopes, T-Lymphocyte, Female, Immunodominant Epitopes, Mice, Mice, Inbred BALB C, Plasmids, Respiratory Syncytial Virus Vaccines, Respiratory Syncytial Viruses, Vaccines, DNA, Viral Proteins
Show Abstract · Added August 6, 2012
Cytotoxic T lymphocytes (CTLs) are critical for the control of respiratory syncytial virus infection (RSV) in humans and mice. Recently, we identified a new H-2K(d)-restricted subdominant epitope in the respiratory syncytial virus M2 protein. In this study, we investigated if modification of anchor residues at positions 2 and 9 in the dominant M2(82-90) epitope in the M2 protein would alter the CTL epitope dominance hierarchy following immunization with plasmid DNA encoding M2 proteins. We showed that immunogenicity of the subdominant epitope M2(127-135) was enhanced when the anchor residues of the dominant epitope were mutated, suggesting that the immunodominant epitope induces a suppression of response to the subdominant epitope.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Functional maturation of the human antibody response to rotavirus.
Kallewaard NL, McKinney BA, Gu Y, Chen A, Prasad BV, Crowe JE
(2008) J Immunol 180: 3980-9
MeSH Terms: Antibodies, Viral, Antigens, Viral, Binding Sites, Antibody, Capsid Proteins, Humans, Immunodominant Epitopes, Immunoglobulin D, Immunoglobulin Fab Fragments, Immunoglobulin Heavy Chains, Immunoglobulin Variable Region, Kinetics, Respiratory Syncytial Viruses, Rotavirus, Somatic Hypermutation, Immunoglobulin
Show Abstract · Added August 6, 2012
Infant Abs induced by viruses exhibit poor functional activity compared with those of adults. The human B cell response to rotavirus is dominated by use of the V(H)1-46 gene segment in both adults and infants, but only adult sequences are highly mutated. We investigated in detail the kinetic, structural, and functional advantage conferred by individual naturally occurring somatic mutations in rotavirus-specific human Abs encoded by the immunodominant V(H)1-46 gene segment. Adult Abs achieved enhanced binding through naturally occurring somatic mutations in the H chain CDR2 region that conferred a markedly prolonged off-rate and a desirable increase in antiviral potency. Three-dimensional cryoelectron microscopy studies of Ag-Ab complexes revealed the mechanism of viral inhibition to be the binding of high-affinity Abs at the viral RNA release pore in the double-layer particle. These structure-function studies suggest a molecular basis for the poor quality of Abs made in infancy following virus infection or immunization.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Immunodominance of the VH1-46 antibody gene segment in the primary repertoire of human rotavirus-specific B cells is reduced in the memory compartment through somatic mutation of nondominant clones.
Tian C, Luskin GK, Dischert KM, Higginbotham JN, Shepherd BE, Crowe JE
(2008) J Immunol 180: 3279-88
MeSH Terms: Adult, Antibodies, Viral, Antigens, Viral, B-Lymphocyte Subsets, Capsid Proteins, Clone Cells, Epitopes, B-Lymphocyte, Humans, Immunodominant Epitopes, Immunoglobulin Class Switching, Immunoglobulin Heavy Chains, Immunoglobulin Variable Region, Immunologic Memory, Middle Aged, Resting Phase, Cell Cycle, Rotavirus, Somatic Hypermutation, Immunoglobulin
Show Abstract · Added August 6, 2012
Detailed characterization of Ag-specific naive and memory B cell Ab repertoires elucidates the molecular basis for the generation of Ab diversity and the optimization of Ab structures that bind microbial Ags. In this study, we analyzed the immunophenotype and VH gene repertoire of rotavirus (RV) VP6-specific B cells in three circulating naive or memory B cell subsets (CD19+IgD+CD27-, CD19+IgD+CD27+, or CD19+IgD-CD27+) at the single-cell level. We aimed to investigate the influence of antigenic exposure on the molecular features of the two RV-specific memory B cell subsets. We found an increased frequency of CD19+IgD+CD27+ unclass-switched memory B cells and a low frequency of somatic mutations in CD19+IgD-CD27+ class-switched memory B cells in RV-specific memory B cells, suggesting a reduced frequency of isotype switching and somatic mutation in RV VP6-specific memory B cells compared with other memory B cells. Furthermore, we found that dominance of the VH1-46 gene segment was a prominent feature in the VH gene repertoire of RV VP6-specific naive B cells, but this dominance was reduced in memory B cells. Increased diversity in the VH gene repertoire of the two memory B cell groups derived from broader usage of VH gene segments, increased junctional diversity that was introduced by differential TdT activities, and somatic hypermutation.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Escape from the dominant HLA-B27-restricted cytotoxic T-lymphocyte response in Gag is associated with a dramatic reduction in human immunodeficiency virus type 1 replication.
Schneidewind A, Brockman MA, Yang R, Adam RI, Li B, Le Gall S, Rinaldo CR, Craggs SL, Allgaier RL, Power KA, Kuntzen T, Tung CS, LaBute MX, Mueller SM, Harrer T, McMichael AJ, Goulder PJ, Aiken C, Brander C, Kelleher AD, Allen TM
(2007) J Virol 81: 12382-93
MeSH Terms: Amino Acid Sequence, Capsid, Cyclosporine, HIV Infections, HIV-1, HLA-B27 Antigen, Humans, Immunodominant Epitopes, Molecular Sequence Data, Mutation, T-Lymphocytes, Cytotoxic, Virus Replication, gag Gene Products, Human Immunodeficiency Virus
Show Abstract · Added February 19, 2015
Human leukocyte antigen (HLA)-B27-positive subjects are uncommon in their ability to control infection with human immunodeficiency virus type 1 (HIV-1). However, late viral escape from a narrowly directed immunodominant Gag-specific CD8(+) T-lymphocyte (CTL) response has been linked to AIDS progression in these individuals. Identifying the mechanism of the immune-mediated control may provide critical insights into HIV-1 vaccine development. Here, we illustrate that the CTL escape mutation R(264)K in the HLA-B27-restricted KK10 epitope in the capsid resulted in a significant defect in viral replication in vitro. The R(264)K variant was impaired in generating late reverse transcription products, indicating that replication was blocked at a postentry step. Notably, the R(264)K mutation was associated in vivo with the development of a rare secondary mutation, S(173)A, which restored viral replication in vitro. Furthermore, infectivity of the R(264)K variant was rescued by the addition of cyclosporine A or infection of a cyclophilin A-deficient cell line. These data demonstrate a severe functional defect imposed by the R(264)K mutation during an early step in viral replication that is likely due to the inability of this variant to replicate efficiently in the presence of normal levels of cyclophilin A. We conclude that the impact of the R(264)K substitution on capsid structure constrains viral escape and enables long-term maintenance of the dominant CTL response against B27-KK10, providing an explanation for the protective effect of HLA-B27 during HIV infection.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Tissue-specific regulation of CD8+ T-lymphocyte immunodominance in respiratory syncytial virus infection.
Lee S, Miller SA, Wright DW, Rock MT, Crowe JE
(2007) J Virol 81: 2349-58
MeSH Terms: Amino Acid Sequence, Animals, Antigens, Viral, CD8-Positive T-Lymphocytes, Female, H-2 Antigens, Humans, Immunodominant Epitopes, Interferon-gamma, Mice, Mice, Inbred BALB C, Respiratory Syncytial Virus Infections, Respiratory Syncytial Virus, Human, Viral Matrix Proteins
Show Abstract · Added August 6, 2012
Cytotoxic T lymphocytes (CTLs) are critical for control of respiratory syncytial virus (RSV) infection in humans and mice. To investigate cellular immune responses to infection, it is important to identify major histocompatibility complex (MHC) class I-restricted CTL epitopes. In this study, we identified a new RSV-specific, H-2K(d)-restricted subdominant epitope in the M2 protein, M2(127-135) (amino acids 127 to 135). This finding allowed us to study the frequency of T lymphocytes responding to two H-2K(d)-presented epitopes in the same protein following RSV infection by enzyme-linked immunospot (ELISPOT) and intracellular cytokine assays for both lymphoid and nonlymphoid tissues. For the subdominant epitope, we identified an optimal nine-amino-acid peptide, VYNTVISYI, which contained an H-2K(d) consensus sequence with Y at position 2 and I at position 9. In addition, an MHC class I stabilization assay using TAP-2-deficient RMA-S cells transfected with K(d) or L(d) indicated that the epitope was presented by K(d). The ratios of T lymphocytes during the peak CTL response to RSV infection that were specific for M2(82-90) (dominant) to T lymphocytes specific for M2(127-135) (subdominant) were approximately 3:1 in the spleen and 10:1 in the lung. These ratios were observed consistently in primary or secondary infection by the ELISPOT assay and in secondary infection by MHC/peptide tetramer staining. The number of antigen-specific T lymphocytes dropped in the 6 weeks after infection; however, the proportions of T lymphocytes specific for the immunodominant and subdominant epitopes were maintained to a remarkable degree in a tissue-specific manner. These studies will facilitate investigation of the regulation of immunodominance of RSV-specific CTL epitopes.
0 Communities
1 Members
0 Resources
14 MeSH Terms