Postdoctoral Position Available

Kenneth Rock, M.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Pathology

Other Affiliation(s):
   Center for AIDS Research
   Program in Immunology and Virology

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 and  more  generally 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.

Representative Publications:

Michalek, M.T., Grant E. Gramm, C., Goldberg, and Rock, K.L. A role for the ubiquitin-dependent proteolytic pathway in MHC class I-restricted antigen presentation. 1993. Nature. 363: 552-554.

Rock, K.L., Gramm, C., Rothstein, L., Clark  , K., Stein, R., Dick, L., Hwang, D., and Goldberg, A.L. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC-class I molecules. 1994. Cell. 78: 761-771.

Kovacsovics-Bankowski, M., and Rock, K.L. A phagosome-to-cytosol pathway for exogenous antigens presented on MHC class I molecules. 1995. Science. 267: 243-246.

Falo, L.D., Jr., Kovacsovics-Bankowski, M., Thompson, K., and Rock, K.L. Vaccination with particulate antigen induces protective tumor immunity. 1995. Nature Medicine. 1: 649-653.

Craiu, A. Akopian, T., Goldberg, A., and Rock, K.L. Two distinct proteolytic processes in the generation of an MHC class I-presented peptide. 1997. Proc. Natl. Acad. Sci. USA. 94: 10850-10855

Sigal, LJ, Crotty, S., Andino, R., and Rock, K.L. Cytotoxic T cell immunity to virus-infected non-haematopoietic cells requires presentation of exogenous antigen. 1999. Nature. 398: 77-80.

York, I.A., Chang, S-C., Saric, T., Keys, J.A., Favreau, J.M., Goldberg, A.L. and Rock, K.L. The interferon-inducible ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming peptides to 8-9 residues. 2002 Nature Immunology, 3: 1177-1184

York, IA, Mo, AXY, Lemerise, K., Zeng, W., Shen, Y., Abraham, CR. Goldberg, A and Rock, KL. Thimet oligopeptidase can degrade antigenic peptides in the cytosol and limit MHC class I antigen presentation 2003 Immunity, 18: 429-40.

Shi, Y., Evans, JE. and Rock, KL. Molecular identification of a danger signal that alerts the immune system to dying cells. 2003 Nature, 425: 516-21

Shen, L., Sigal, LJ. Boes, M., and Rock, KL. Critical role of cathepsin S in TAP-independent MHC class I cross presentation in vivo. 2004 Immunity. 45: 218-25

Rock, KL., York  , I., and Goldberg, AL. 2004.  Post-proteasomal antigen processing for MHC class I presentation.  Nature Immunololgy. 5: 670-77

Shi, Y, Galusha, SA., and Rock KL. 2006 Elimination of an endogenous adjuvant reduces the activation of CD8 T lymphocytes to transplanted cells and in an autoimmune diabetes model. J. Immunol. Cutting Edge 176: 3905-08

York, IA, Brehm, MA, Zendzian, S., Towne, CF., and Rock, KL. 2006 ER-Aminopeptidase I (ERAP1) trims MHC class I-presented peptides in vivo and plays an important role in establishing immunodominance. Proc. Natl. Acad. Sci. USA. 103: 9202-7

Chen, C-J., Shi, Y., Hearn, A., Fitzgerald, K., Golenbock, D., Akira, S., and Rock, K.L. 2006 MyD88-dependent interleukin 1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J. Clin Invest. 116:2262-71.

Chen, C-J., Kono, H., Golenbock, D., Reed, G., Akira, S., and Rock, K.L. 2007. Identification of a key pathway required for the sterile inflammatory response triggered by necrotic dying cells. Nature Medicine. 13:851-6

Rock, KL. and Kono, H. 2008. How dying cells alert the immune system to danger. Nature Rev. Immunol. 8:279-89

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.

Academic Background

MD, 1978, University of Rochester

Office: S2-109
Phone: 508-856-2521
E-mail: Kenneth.Rock@umassmed.edu
Keywords: Immunology, Cell Biology, Virology

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Postdoctoral Position Available A postdoctoral position is available to study in this laboratory. Contact Dr. Rock for additional details.