Home Faculty and Research Faculty by Name Nilabh Shastri

Nilabh Shastri

Professor of Immunology and Pathogenesis

Lab Homepage: http://mcb.berkeley.edu/labs/shastri/

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Research Interests

How the immune system detects and eliminates “foreign” microbial pathogens or cancer cells is intriguing.  Regrettably, the immune system can also reject transplants and self-tissues in autoimmunity. We study molecular mechanisms that cause cells to become uniquely foreign to the immune system.

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 distinct from our own cells, but the differences are often hidden deep inside the cells’ genome.  To allow the killer cells of the immune system to survey these differences, virtually all cells have the remarkable ability (called antigen presentation) to reveal their intracellular contents in the form of short antigenic peptides (p) which are chaperoned by MHC molecules to their surface (pMHC, see figure).  These pMHC molecules include peptides derived from the new proteins, for example, a viral protein in the infected cell or a mutant protein in a cancer cell.  The killer T cells have evolved to recognize individual pMHC using their antigen receptors.  The pMHC thus acts as a flag to activate the killer T cell and eventually eliminate the undesirable “foreign” cell.   Unfortunately, the same mechanism also rejects transplanted organs, despite their desirability to the recipient and can cause autoimmunity.  The particular peptides that set off the killer T cells and the mechanisms that generate these pMHC are poorly understood.

To identify unknown T cell activating peptides, we developed the "lacZ" assay for measuring pMHC-specific T cell activation. T-cells harboring the inducible β-galactosidase (lacZ) reporter gene serve as exquisite probes for detecting the pMHC on the cell surface. Because the pMHC are generated when the antigen gene is transferred into cells, we screen DNA libraries to isolate the relevant gene that encodes the T cell antigen. This expression cloning method has revealed the identity of many T antigens from tumors, pathogenic microbes and transplanted tissues. Intriguingly, the antigenic peptides are encoded not only in conventional "open" but also in "non-coding" cryptic translational reading frames.  We are studying the yet unknown translation initiation mechanism that generates these unique peptides and their role in eliciting T cell immunity.

We study pMHC presentation pathway by cellular, genetic and biochemical approaches.  The naturally processed peptides are analyzed in cells by high performance liquid chromatography using T cell assays. By manipulating the genes for the antigen, as well as other chaperones and proteases we have defined key steps in the intracellular pathways for generating pMHC.  Manipulaton of these intermediate steps results in either inhibiting or enhancing immunogenicity.  We are currently studying how these manipulations impact the immune response in cancer and autoimmunity.

Selected Publications

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] 

The aminopeptidase ERAAP shapes the peptide repertoire displayed by major histocompatibility complex class I molecules. [G.E. Hammer, F. Gonzalez, M. Champsaur, D. Cado and N. Shastri (2005) Nature Immunology 7:103-112] 

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]

Unanticipated antigens: Translational initiation at CUG with a leucine. [S. R. Schwab, J. Shugart, T. Horng, S. Malarkannan, and N. Shastri (2004) PLoS Biology 2:e366]

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) J. Exp. Med.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 2007-02-14