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One or more keywords matched the following properties of Rock, Kenneth
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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 Diversity in MHC class II ovalbumin T cell epitopes generated by distinct proteases.
Academic Article Analysis of the association of peptides of optimal length to class I molecules on the surface of cells.
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 Cytotoxic T-cell immunity to virus-infected non-haematopoietic cells requires presentation of exogenous antigen.
Academic Article Serum proteases alter the antigenicity of peptides presented by class I major histocompatibility complex molecules.
Academic Article Distinct proteolytic processes generate the C and N termini of MHC class I-binding peptides.
Academic Article Reassociation with beta 2-microglobulin is necessary for Db class I major histocompatibility complex binding of an exogenous influenza peptide.
Academic Article Leucine aminopeptidase is not essential for trimming peptides in the cytosol or generating epitopes for MHC class I antigen presentation.
Academic Article 26S proteasomes and immunoproteasomes produce mainly N-extended versions of an antigenic peptide.
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 Analysis of the role of tripeptidyl peptidase II in MHC class I antigen presentation in vivo.
Academic Article Not just research tools--proteasome inhibitors offer therapeutic promise.
Academic Article Rate of antigen degradation by the ubiquitin-proteasome pathway influences MHC class I presentation.
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 Proteases in MHC class I presentation and cross-presentation.
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 Peptide-priming of cytolytic T cell immunity in vivo using beta 2-microglobulin as an adjuvant.
Concept Viral Proteins
Concept Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
Concept Viral Core Proteins
Concept Viral Vaccines
Concept Antigens, Viral
Concept Peptide Hydrolases
Concept Viral Envelope Proteins
Academic Article Present Yourself! By MHC Class I and MHC Class II Molecules.
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