Department of Molecular & Cell Biology

Home Faculty and Research Faculty by Name Nilabh Shastri

Nilabh Shastri

Professor of Immunology and Pathogenesis

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Research Interests

How does the immune system detect and eliminate undesirable pathogens and regrettably, desirable transplants or self-tissues?

Current Projects

How does our immune system know if a virus is lurking inside an infected cell, if a normal cell has turned cancerous or if an organ is transplanted from an unrelated donor?  All these abnormal cells are different from our normal self, but the differences are often hidden deep within the cells’ DNA.  To permit the immune system to detect these differences, our cells have evolved a remarkable function, called antigen presentation, to reveal their intracellular contents on the surface.  Virtually all intracellular proteins are fragmented into small peptides (p) that are chaperoned by MHC molecules to the cell surface (as ‘pMHC’, see figure).  This comprehensive pMHC display includes peptides derived from the new proteins, for example, a viral protein in an infected cell or a mutant protein in a cancer cell.  The killer T cells of the immune system use their antigen receptors to recognize individual pMHC on the surface of target cells.  The pMHC thus acts as a flag for activating killer T cells which eventually eliminate the undesirable ‘foreign’ cell.   Unfortunately, the same mechanisms can also reject transplanted organs and self-tissues in autoimmunity. The unique antigenic peptides that set off the killer T cells and the mechanisms that generate the pMHC in health and disease are poorly understood.

 

 

To identify unknown T cell activating peptides, we developed the ‘lacZ’ assay for measuring pMHC-specific T cell activation.  T-cells containing the inducible β-galactosidase (lacZ) reporter gene are exquisite probes for detecting even rare pMHC producing cells.  Because the pMHC are generated when the antigenic precursor protein is expressed in cells, we can screen DNA libraries to isolate the relevant gene that encodes the T cell antigen. This expression cloning method has revealed the identity of many antigens from pathogenic microbes, parasites, transplanted tissues and cancer cells.  Intriguingly, we discovered that antigenic peptides are encoded not only in conventional ‘open’ but also in ‘non-coding’ cryptic translational reading frames.  Such cryptic peptides play key roles in immunity and perhaps normal cell biology as well.  We are currently studying the novel sources and translation initiation mechanisms that generate these unique peptides and their immunological and biological functions.

We analyze the pMHC presentation pathway using cellular, genetic and biochemical methods for tracking naturally processed peptides in antigen presenting cells.  By manipulating the expression of the antigen, molecular chaperones and proteases we have defined new steps in the pMHC antigen processing and presentation pathways. Remarkably, manipulating the intermediate steps can either inhibit or enhance immunogenicity suggesting new approaches to vaccine design. 

We are currently studying how these manipulations impact the immune responses towards microbes, cancer and self-tissues.

Selected Publications

 

Non-conventional sources of peptides presented by MHC class I  [Starck, S.R. and N. Shastri (2011) Cell. Mol. Life Sci. 68:1471-1479]

ERAAP defines the composition and structure of MHC I peptide repertoire in normal and virus-infected cells. [Blanchard, N., T. Kanaseki, H. Escobar, F. Delebecque, N.A. Nagarajan, E. Reyes-Vargas, D.K. Crockett, D.H. Raulet, J. C. Delgado, N. Shastri (2010). Journal of Immunol. 184: 3033-3042]

 The synthesis of truncated polypeptides for immune surveillance and viral evasion.  [Cardinaud, S., S.R. Starck, P. Chandra and N. Shastri (2010). PLoS ONE 5:e8692]

 Immunodominant, protective response to the parasite Toxoplasma gondii requires antigen processing in the endoplasmic reticulum.  [Blanchard, N., F. Gonzales, M. M. Schaeffer, N. T. Joncker, T. Cheng, A. Shastri, E. A. Robey, N. Shastri (2008). Nature Immunology 9:937-944]

 A distinct translational initiation mechanism generates cryptic peptides for immune surveillance. [Starck, S.R., Y. Ow, V. Jiang, M. Tokuyama, M. Rivera, X. Qi, R.W. Roberts and N. Shastri (2008). PLoS ONE 3:e3460, doi:10.1371]

 In the absence of aminopeptidase ERAAP, MHC class I molecules present many unstable and highly immunogenic peptides. [G.E. Hammer, F. Gonzalez, E. James, H. Nolla and N. Shastri (2007) Nature Immunology 8:101-108]

 Hsp90α chaperones large C-terminally extended proteolytic intermediates in the MHC I antigen processing pathway. [Kunisawa, J. and N. Shastri (2006)  Immunity 24:523-534]

 MHC I molecules constitutively present cryptic translation products. [S. R. Schwab, K. Li, C. Kang and N. Shastri (2003) Science 301:1367-1371]

 ERAAP customizes peptides for presentation by MHC class I molecules in the endoplasmic reticulum. [T. Serwold, F. Gonzalez, J. Kim, R. Jacob and N. Shastri (2002) Nature 419, 480-483]

 Producing nature's gene-chips: The generation of peptides for display by MHC class I molecules. [N. Shastri, S. Schwab and T. Serwold (2002) Annual Reviews in Immunology 20:463-493]

Last Updated 2011-08-18