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Academic Background

MD, 1978, University of Rochester

Mechanisms to control display of foreign antigens to immune system

Our laboratory investigates the mechanisms which control the display of foreign antigens to the immune system andDr. Kenneth Rock - Chair of the Pathology Department moregenerally the process of immune surveillance. In these processes the immune system uses MHC class I molecules to display on the cell surface oligopeptides derived from a cell's expressed genes. This allows cytotoxic T lymphocytes of the immune system to detect and eliminate cells expressing "foreign" sequences (e.g. from a viral infection or mutation). In many cases two distinct antigen presentation pathways are involved in the initial generation of the immune response and in the subsequent identification of the actual tumor or virally infected cell; these two pathways are termed cross presentation and direct presentation.

To initiate responses, antigens must be displayed on class I molecules of professional antigen presenting cells (e.g. dendritic cells). If these cells are not themselves making the antigen, they acquire them from dying cells and present them on class I molecules, through a mechanism called “cross presentation”. In this process tissue antigens are internalized into phagosome of the antigen presenting cells and then can follow two distinct pathways for presentation. We are studying how the antigen presenting cells and their cross presentation pathways work and might be exploited for immunotherapy.

Once cytotoxic T lymphocytes are stimulated they then seek out all cells that are synthesizing the "foreign antigen" and displaying its fragments on class I molecules. This display occurs through the “direct” or “classical” antigen presentation pathway. In this process, the majority of these MHC class I-presented peptides are generated by large proteolytic particles, proteasomes, which are present in the cytoplasm and nucleus of all Eukaryotic cells. These peptides must be of an exact size (8-10 residues) in order to bind to class I molecules. Where examined, the proteasome is responsible for making the proper C-terminal cleavage to produce antigenic peptides, however it often makes N-extended precursors. The precursor peptides can be trimmed to the mature epitope by aminopeptidases in the cytosol or endoplasmic reticulum or destroyed by other peptidases. After they are generated in the cytoplasm a fraction of the peptides are transported into the endoplasmic reticulum where ones of the correct size and sequence are bound by MHC class I molecules and transported to the cell surface for display. These processes determine whether antigens are recognized, the magnitude and specificity of the immune response and ultimately whether abnormal cells are eliminated. We are studying all of these processes in detail.

A related area of investigation concerns how the immune surveillance process is regulated. In order for productive immune responses to be generated, it is necessary for antigen presenting cells to acquire not only antigen but also to mature to an immunostimulatory state. The latter occurs when the antigen presenting cell senses that an antigen is dangerous, e.g. associated with microbial components. In addition, danger signals can be generated by injured and dying cells. We have found that when cancerous or infected cells die they not only release antigens but also endogenous adjuvants that markedly stimulate the generation of T responses. These adjuvants are ordinarily sequestered in the cytosol and are released when the plasma membrane loses integrity. One of these endogenous adjuvants has been identified as uric acid and data suggests that the active form of this molecule is monosodium urate crystals (MSU). There are also other endogenous adjuvants. We are actively studying these molecules, how they function and their role in immune surveillance.

Rotation Projects

Potential Rotation Projects

Rotations are available in Dr. Rock’s laboratory for graduate students in the GSBS program. The rotation projects will explore various aspects of how the immune system carries out surveillance to detect viral infections and cancers. Among the potential areas of research are: (1) The alarm signals that alert the immune system to potential danger; (2) The initial innate immune and inflammatory response to infection or other dangerous situations; (3) The biology of the sentinel cells (e.g. dendritic cells) that sense danger and report it the adaptive immune system; (4) The mechanisms by which sentinel cells (e.g. dendritic cells) acquire and display antigens to T cells; and, (5) The antigen presentation pathways by which virally infected or cancer cells display a sampling of their expressed gene products to the activated T cells. Specific rotation projects are chosen based on the student’s interests and state/availability of the various projects in the laboratory. The goals of rotations are for the student to gain knowledge in immunology, to learn how to approach experimental problems, to learn new techniques and methods, and to actually generate data that moves our knowledge forward. In addition, the rotation provides the student the opportunity to evaluate the laboratory as a possible place to conduct their thesis research in the future.


One or more keywords matched the following items that are connected to Rock, Kenneth

Item TypeName
Academic Article Analysis of MHC class II presentation of particulate antigens of B lymphocytes.
Academic Article Proteasome subunits X and Y alter peptidase activities in opposite ways to the interferon-gamma-induced subunits LMP2 and LMP7.
Academic Article Internalization of glycosyl-phosphatidylinositol (GPI)-anchored lymphocyte proteins. II. GPI-anchored and transmembrane molecules internalize through distinct pathways.
Academic Article Diversity in MHC class II ovalbumin T cell epitopes generated by distinct proteases.
Academic Article Processing and presentation of ovalbumin in mice genetically selected for antibody response.
Academic Article CD4+ T cells mature in the absence of MHC class I and class II expression in Ly-6A.2 transgenic mice.
Academic Article Poliovirus vaccine vectors elicit antigen-specific cytotoxic T cells and protect mice against lethal challenge with malignant melanoma cells expressing a model antigen.
Academic Article Chemical denaturation and modification of ovalbumin alters its dependence on ubiquitin conjugation for class I antigen presentation.
Academic Article Heterogeneity in antigen processing by different types of antigen-presenting cells. Effect of cell culture on antigen processing ability.
Academic Article A monoclonal antibody reactive with a 40-kDa molecule on fetal thymocytes and tumor cells blocks proliferation and stimulates aggregation and apoptosis.
Academic Article Sequences that flank subdominant and cryptic epitopes influence the proteolytic generation of MHC class I-presented peptides.
Academic Article Major histocompatibility class I presentation of soluble antigen facilitated by Mycobacterium tuberculosis infection.
Academic Article Cloned dendritic cells can present exogenous antigens on both MHC class I and class II molecules.
Academic Article Lactacystin and clasto-lactacystin beta-lactone modify multiple proteasome beta-subunits and inhibit intracellular protein degradation and major histocompatibility complex class I antigen presentation.
Academic Article Analysis of the association of peptides of optimal length to class I molecules on the surface of cells.
Academic Article Two distinct proteolytic processes in the generation of a major histocompatibility complex class I-presented peptide.
Academic Article Cell death releases endogenous adjuvants that selectively enhance immune surveillance of particulate antigens.
Academic Article Stimulation of B lymphocytes through surface Ig receptors induces LFA-1 and ICAM-1-dependent adhesion.
Academic Article Effect of ras-activation on the expression of glycosyl-phosphatidylinositol-anchored proteins on the plasma membrane.
Academic Article Interferon-gamma can stimulate post-proteasomal trimming of the N terminus of an antigenic peptide by inducing leucine aminopeptidase.
Academic Article The role of B7-1 and B7-2 costimulation for the generation of CTL responses in vivo.
Academic Article Fully mobilizing host defense: building better vaccines.
Academic Article MHC class I-restricted presentation of exogenous antigen by thymic antigen-presenting cells in vitro and in vivo.
Academic Article The cytosolic endopeptidase, thimet oligopeptidase, destroys antigenic peptides and limits the extent of MHC class I antigen presentation.
Academic Article Cytotoxic T-cell immunity to virus-infected non-haematopoietic cells requires presentation of exogenous antigen.
Academic Article Molecular identification of a danger signal that alerts the immune system to dying cells.
Academic Article Class II antigen processing defects in two H2d mouse cell lines are caused by point mutations in the H2-DMa gene.
Academic Article Degradation of cell proteins and the generation of MHC class I-presented peptides.
Academic Article Serum proteases alter the antigenicity of peptides presented by class I major histocompatibility complex molecules.
Academic Article Natural endogenous adjuvants.
Academic Article Chemical cross-linking of class I molecules on cells creates receptive peptide binding sites.
Academic Article Reassociation with beta 2-microglobulin is necessary for Db class I major histocompatibility complex binding of an exogenous influenza peptide.
Academic Article Both dendritic cells and macrophages can stimulate naive CD8 T cells in vivo to proliferate, develop effector function, and differentiate into memory cells.
Academic Article Cross-presentation: underlying mechanisms and role in immune surveillance.
Academic Article Dissociation of beta 2-microglobulin leads to the accumulation of a substantial pool of inactive class I MHC heavy chains on the cell surface.
Academic Article Leucine aminopeptidase is not essential for trimming peptides in the cytosol or generating epitopes for MHC class I antigen presentation.
Academic Article Priming of T cells by exogenous antigen cross-presented on MHC class I molecules.
Academic Article Characterization of MHC class II-presented peptides generated from an antigen targeted to different endocytic compartments.
Academic Article Inhibition of class I and class II MHC-restricted antigen presentation by cytotoxic T lymphocytes specific for an exogenous antigen.
Academic Article Bone marrow-derived antigen-presenting cells are required for the generation of cytotoxic T lymphocyte responses to viruses and use transporter associated with antigen presentation (TAP)-dependent and -independent pathways of antigen presentation.
Academic Article Cell injury releases endogenous adjuvants that stimulate cytotoxic T cell responses.
Academic Article Anti-peptide antibody blocks peptide binding to MHC class I molecules in the endoplasmic reticulum.
Academic Article Exiting the outside world for cross-presentation.
Academic Article CD40-CD40 ligand interaction between dendritic cells and CD8+ T cells is needed to stimulate maximal T cell responses in the absence of CD4+ T cell help.
Academic Article Identification of a key pathway required for the sterile inflammatory response triggered by dying cells.
Academic Article Pillars article: antigen presentation by hapten-specific B lymphocytes. I. Role of surface immunoglobulin receptors. 1984.
Academic Article The inflammatory response to cell death.
Academic Article Puromycin-sensitive aminopeptidase limits MHC class I presentation in dendritic cells but does not affect CD8 T cell responses during viral infections.
Academic Article Major histocompatibility complex class I-presented antigenic peptides are degraded in cytosolic extracts primarily by thimet oligopeptidase.
Academic Article An oncofetal protein IMP3: a new molecular marker for the detection of esophageal adenocarcinoma and high-grade dysplasia.
Academic Article Antigen presentation by hapten-specific B lymphocytes. II. Specificity and properties of antigen-presenting B lymphocytes, and function of immunoglobulin receptors.
Academic Article Pathobiology of inflammation to cell death.
Academic Article Analysis of antigen presentation by metabolically inactive accessory cells and their isolated membranes.
Academic Article The expression, function, and ontogeny of a novel T cell-activating protein, TAP, in the thymus.
Academic Article The specificity of trimming of MHC class I-presented peptides in the endoplasmic reticulum.
Academic Article Analysis of the role of tripeptidyl peptidase II in MHC class I antigen presentation in vivo.
Academic Article Stimulation of human Jurkat cells by monoclonal antibody crosslinking of transfected-Ly-6A.2 (TAP) molecules.
Academic Article The sterile inflammatory response.
Academic Article Characterizing the specificity and cooperation of aminopeptidases in the cytosol and endoplasmic reticulum during MHC class I antigen presentation.
Academic Article Uric acid promotes an acute inflammatory response to sterile cell death in mice.
Academic Article Not just research tools--proteasome inhibitors offer therapeutic promise.
Academic Article Placental leucine aminopeptidase efficiently generates mature antigenic peptides in vitro but in patterns distinct from endoplasmic reticulum aminopeptidase 1.
Academic Article Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy.
Academic Article The LY-6 locus: a multigene family encoding phosphatidylinositol-anchored membrane proteins concerned with T-cell activation.
Academic Article Innate and adaptive immune responses to cell death.
Academic Article T cell receptor/CD3 negative variants are unresponsive to stimulation through the Ly-6 encoded molecule, TAP.
Academic Article Structural characterization of the TAP molecule: a phosphatidylinositol-linked glycoprotein distinct from the T cell receptor/T3 complex and Thy-1.
Academic Article The IL-1-dependent sterile inflammatory response has a substantial caspase-1-independent component that requires cathepsin C.
Academic Article Low temperature and peptides favor the formation of class I heterodimers on RMA-S cells at the cell surface.
Academic Article Using intein catalysis to probe the origin of major histocompatibility complex class I-presented peptides.
Academic Article The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8-9 residues.
Academic Article The class II MHC-restricted presentation of endogenously synthesized ovalbumin displays clonal variation, requires endosomal/lysosomal processing, and is up-regulated by heat shock.
Academic Article Gene encoding T-cell-activating protein TAP maps to the Ly-6 locus.
Academic Article Expression of T-cell-activating protein in peripheral lymphocyte subsets.
Academic Article Stimulation of T cells via the TAP molecule, a member in a family of activating proteins encoded in the Ly-6 locus.
Academic Article Characterization of antigen association with accessory cells: specific removal of processed antigens from the cell surface by phospholipases.
Academic Article Phospholipase treatment of accessory cells that have been exposed to antigen selectively inhibits antigen-specific Ia-restricted, but not allospecific, stimulation of T lymphocytes.
Academic Article The ins and outs of cross-presentation.
Academic Article Characterization of the proliferative response of a CD4-8- thymic T lymphoma cell line to stimulation by thymic cellular elements.
Academic Article Inhibition of antigen-specific T lymphocyte activation by structurally related Ir gene-controlled polymers. Evidence of specific competition for accessory cell antigen presentation.
Academic Article Antigen presentation by hapten-specific B lymphocytes. I. Role of surface immunoglobulin receptors.
Academic Article Two distinct mechanisms regulate the in vivo generation of cytotoxic T cells.
Academic Article MHC-restricted T cell activation: analysis with T cell hybridomas.
Academic Article The role of Ia molecules in the activation of T lymphocytes. III. Antigen-specific, Ia-restricted, interleukin 2-producing T cell hybridomas with detectable affinity for the restricting I-A molecule.
Academic Article Rate of antigen degradation by the ubiquitin-proteasome pathway influences MHC class I presentation.
Academic Article Regulated expression of Ly-6A.2 is important for T cell development.
Academic Article Overexpressed Ly-6A.2 mediates cell-cell adhesion by binding a ligand expressed on lymphoid cells.
Academic Article Presentation of exogenous antigens by macrophages: analysis of major histocompatibility complex class I and II presentation and regulation by cytokines.
Academic Article Peptidase activities of proteasomes are differentially regulated by the major histocompatibility complex-encoded genes for LMP2 and LMP7.
Academic Article Gamma-interferon and expression of MHC genes regulate peptide hydrolysis by proteasomes.
Academic Article Characterization of antigen-presenting cells that present exogenous antigens in association with class I MHC molecules.
Academic Article Efficient major histocompatibility complex class I presentation of exogenous antigen upon phagocytosis by macrophages.
Academic Article Proteolysis, proteasomes and antigen presentation.
Academic Article The generation of immunogenic peptides can be selectively increased or decreased by proteolytic enzyme inhibitors.
Academic Article Role of ICAM-1 in antigen presentation demonstrated by ICAM-1 defective mutants.
Academic Article Weak base amines can inhibit class I MHC-restricted antigen presentation.
Academic Article A mutant cell with a novel defect in MHC class I quality control.
Academic Article Characterization of a proapoptotic antiganglioside GM2 monoclonal antibody and evaluation of its therapeutic effect on melanoma and small cell lung carcinoma xenografts.
Academic Article Cutting edge: elimination of an endogenous adjuvant reduces the activation of CD8 T lymphocytes to transplanted cells and in an autoimmune diabetes model.
Academic Article Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims MHC class I-presented peptides in vivo and plays an important role in immunodominance.
Academic Article Analysis of RNA-binding protein IMP3 to predict metastasis and prognosis of renal-cell carcinoma: a retrospective study.
Academic Article Tripeptidyl peptidase II is the major peptidase needed to trim long antigenic precursors, but is not required for most MHC class I antigen presentation.
Academic Article Analysis of the role of bleomycin hydrolase in antigen presentation and the generation of CD8 T cell responses.
Academic Article Reassociation with beta 2-microglobulin is necessary for Kb class I major histocompatibility complex binding of exogenous peptides.
Academic Article How dying cells alert the immune system to danger.
Academic Article CD40 on APCs is needed for optimal programming, maintenance, and recall of CD8+ T cell memory even in the absence of CD4+ T cell help.
Academic Article Oncofetal protein IMP3: a novel molecular marker that predicts metastasis of papillary and chromophobe renal cell carcinomas.
Academic Article Combination of quantitative IMP3 and tumor stage: a new system to predict metastasis for patients with localized renal cell carcinomas.
Academic Article Presentation of exogenous antigen with class I major histocompatibility complex molecules.
Academic Article TAP, a novel T cell-activating protein involved in the stimulation of MHC-restricted T lymphocytes.
Academic Article Two genetically identical antigen-presenting cell clones display heterogeneity in antigen processing.
Academic Article Identification of the cellular sensor that stimulates the inflammatory response to sterile cell death.
Academic Article Internalization of phosphatidylinositol-anchored lymphocyte proteins. I. Documentation and potential significance for T cell stimulation.
Academic Article The importance of antigen processing in determinant selection and of the cell membrane as a reservoir of processed antigen.
Academic Article Oncofetal protein IMP3, a new diagnostic biomarker to distinguish malignant mesothelioma from reactive mesothelial proliferation.
Academic Article IMP3, a new biomarker to predict progression of cervical intraepithelial neoplasia into invasive cancer.
Academic Article Mice completely lacking immunoproteasomes show major changes in antigen presentation.
Academic Article A novel approach to recovery of function of mutant proteins by slowing down translation.
Academic Article TAP transcription and phosphatidylinositol linkage mutants are defective in activation through the T cell receptor.
Academic Article Cloning and expression of a cDNA for the T-cell-activating protein TAP.
Academic Article Antigen presentation by hapten-specific B lymphocytes. III. Analysis of the immunoglobulin-dependent pathway of antigen presentation to interleukin 1-dependent T lymphocytes.
Academic Article T cell-activating protein on murine lymphocytes.
Academic Article Biosynthesis, glycosylation, and partial N-terminal amino acid sequence of the T-cell-activating protein TAP.
Academic Article Cerulenin is a potent inhibitor of antigen processing by antigen-presenting cells.
Academic Article Self antigenic mimicry and Ir gene control of T cell responsiveness--a commentary.
Academic Article Selective modification of a private I-A allo-stimulating determinant(s) upon association of antigen with an antigen-presenting cell.
Academic Article Analysis of thymocyte MHC specificity with thymocyte hybridomas.
Academic Article Inhibition of antigen-specific T lymphocyte activation by structurally related Ir gene-controlled polymers. II. Competitive inhibition of I-E-restricted, antigen-specific T cell responses.
Academic Article Selection of thymocyte MHC restriction specificity in vitro.
Academic Article The role of H-2 linked genes in helper T-cell function. II. Isolation on antigen-pulsed macrophages of two separate populations of F1 helper T cells each specific for antigen and one set of parental H-2 products.
Academic Article The role of Ia molecules in the activation of T lymphocytes. IV. The basis of the thymocyte IL 1 response and its possible role in the generation of the T cell repertoire.
Academic Article Thymic T cells are driven to expand upon interaction with self-class II major histocompatibility complex gene products on accessory cells.
Academic Article The role of Ia molecules in the activation of T lymphocytes. I. The activation of an IL 1-dependent IL 2-producing T cell hybridoma by Con A requires an interaction, which is not H-2-restricted, with an Ia-bearing accessory cell.
Academic Article Antibody responses to trinitrophenyl (TNP)-L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) in microcultures: anti-hapten and anti-carrier responses appear to be under separable control.
Academic Article Altered peptidase and viral-specific T cell response in LMP2 mutant mice.
Academic Article Gamma-interferon causes a selective induction of the lysosomal proteases, cathepsins B and L, in macrophages.
Academic Article A phagosome-to-cytosol pathway for exogenous antigens presented on MHC class I molecules.
Academic Article Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules.
Academic Article Peptide-priming of cytolytic T cell immunity in vivo using beta 2-microglobulin as an adjuvant.
Academic Article A role for the ubiquitin-dependent proteolytic pathway in MHC class I-restricted antigen presentation.
Academic Article A mutant antigen-presenting cell defective in antigen presentation expresses class II MHC molecules with an altered conformation.
Concept Cell Fusion
Concept Receptors, Antigen, T-Cell, alpha-beta
Concept Receptors, Antigen, T-Cell
Concept Hela Cells
Concept Cell Division
Concept COS Cells
Concept Cell Communication
Concept Mast-Cell Sarcoma
Concept Cell Adhesion Molecules
Concept Receptors, Cell Surface
Concept Cell Adhesion
Concept Jurkat Cells
Concept Dendritic Cells
Concept Cell Aggregation
Concept 3T3 Cells
Concept Tumor Cells, Cultured
Concept Cell Differentiation
Concept Cell Line, Transformed
Concept Bone Marrow Cells
Concept Lymphoma, T-Cell
Concept Cell Movement
Concept Cells, Cultured
Concept Stem Cells
Concept Cell Separation
Concept Cell Proliferation
Concept Hematopoietic Stem Cells
Concept Cell Death
Concept Cell Membrane
Concept Clone Cells
Concept Cell Transformation, Neoplastic
Concept Carcinoma, Renal Cell
Concept Carcinoma, Squamous Cell
Concept Antigen-Presenting Cells
Concept Embryonic Stem Cells
Concept Cell Line
Concept Cell Compartmentation
Concept Cells
Concept Mast Cells
Concept Receptors, Antigen, B-Cell
Concept Carcinoma, Small Cell
Concept Cell Line, Tumor
Academic Article Substrate-induced protein stabilization reveals a predominant contribution from mature proteins to peptides presented on MHC class I.
Academic Article Evaluation of the contribution of multiple DAMPs and DAMP receptors in cell death-induced sterile inflammatory responses.
Academic Article The xanthine oxidase inhibitor Febuxostat reduces tissue uric acid content and inhibits injury-induced inflammation in the liver and lung.
Academic Article The Combined Deficiency of Immunoproteasome Subunits Affects Both the Magnitude and Quality of Pathogen- and Genetic Vaccination-Induced CD8+ T Cell Responses to the Human Protozoan Parasite Trypanosoma cruzi.
Academic Article Specialized proteasome subunits have an essential role in the thymic selection of CD8(+) T cells.
Academic Article Frontline Science: Multiple cathepsins promote inflammasome-independent, particle-induced cell death during NLRP3-dependent IL-1ß activation.
Academic Article Immune Sensing of Cell Death through Recognition of Histone Sequences by C-Type Lectin-Receptor-2d Causes Inflammation and Tissue Injury.

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