Nilabh Shastri

Professor of Immunology and Pathogenesis

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Research Interests

How does the immune system detect and eliminate undesirable pathogens or regrettably, desirable transplants and 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 cells are different from our normal self, but the differences are often hidden deep within the cells’ genome.  To permit the immune system to detect these differences, all cells have evolved a remarkable capacity, called antigen presentation, to reveal intracellular contents on the surface.  Virtually all intracellular proteins are fragmented into small peptides (p) which are chaperoned by MHC molecules to the cell surface (as ‘pMHC’, see figure).  These pMHC molecules include 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 recognize individual pMHC using their antigen receptors.  The pMHC thus acts as a flag for activating the killer T cells which eventually eliminate the undesirable ‘foreign’ cell.   Unfortunately, the same mechanisms also reject transplanted organs and self-tissues in autoimmunity. The particular antigenic peptides that set off the killer T cells and the mechanisms that generate the pMHC not well 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 on the cell surface.  Because the pMHC are generated when the antigen gene 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 and role of many antigens from pathogenic microbes, 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.  We are studying the novel sources and translation mechanisms that generates these unique peptides and their role in eliciting immunity to viruses and cancer.

We study the pMHC presentation pathway using cellular, genetic and biochemical methods for tracking naturally processed peptides in antigen presenting cells.  By manipulating the genes for the antigen, chaperones and proteases we have defined key steps in the antigen processing pathways for generating pMHC.  Interestingly, manipulating the intermediate steps can either inhibit or enhance immunogenicity.  We are learning how these manipulations impact the immune responses towards microbes, cancer and self-tissues.

Selected Publications

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]  

ERAAP synergizes with MHC I to make the final cut in the antigenic peptide precursors in the endoplasmic reticulum. [Kanaseki, T., N. Blanchard, G. Hammer, F. Gonzalez and N. Shastri (2006) Immunity 25:795-806]

All the peptides that fit.  The beginning, the middle, and the end of the MHC class I antigen processing pathway. [N. Shastri, S. Cardinaud, S. R. Schwab, T. Serwold and J. Kunisawa (2005) Immunological Reviews 207:31-41]

The Group II chaperonin TriC protects antigenic intermediates from degradation in the MHC class I antigen processing pathway. [J. Kunisawa and N. Shastri (2003) Molecular Cell 12:565-576]  

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

Second class minors. Molecular identification of the autosomal H46 histocompatibility locus as a peptide presented by MHC class II molecules. [H. Sahara and N. Shastri (2003) Journal of Experimental Medicine 197:375-385]

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]

Differences that matter: Major cytotoxic T cell stimulating minor histocompatibility antigens. [S. Malarkannan, T. Horng, P. Eden, F. Gonzalez, P. Shih, N. Brouwenstijn, D. Roopenian and N. Shastri (2000) Immunity 13:333-344]

Last Updated 2009-08-17