Our laboratory’s research interests lie in four areas: antigen presentation by MHC I and MHC II molecules, immune response to cancer, viral immunity, and autoimmunity. Our pursuit of these areas is linked to a key set of observations made by our laboratory over the past 20 years. These observations are: (1) Heat shock proteins (HSP) isolated from cells are always associated with a broad array of peptides. These peptides are derived from the proteins present in the cell and together, the HSP-associated peptide profile represents the total protein/peptide repertoire of a cell including the antigenic repertoire. (2) The HSP-peptide complexes, whether isolated from cells, or reconstituted in vitro, are potent immunogens against the peptides and cells presenting those peptides. The immune response elicited by such complexes is heavily skewed towards a cellular T cell response. (3) HSPs have remarkable immunomodulatory properties which derive from their interaction with macrophage and dendritic cells through a receptor, identified by us as CD91. Our laboratory has used these observations to explore new key aspects of antigen presentation and to develop innovative approaches for therapy of cancer, infections and autoimmune disorders. It is our view that the HSP-peptide interaction is an evolutionary precursor to the MHC-peptide interaction and lies at the center of a wide array of immunological phenomena.

Lab Rotation Projects:
The following constitutes most of what we do. Students are encouraged to create rotation projects out of any of these areas.

(1) We study antigen presentation and cross-priming. We have uncovered a key role of heat shock proteins, the most highly conserved and abundant proteins in living systems, in both of these phenomena, which are central to immunology.

(2) Our studies with heat shock proteins have lead to novel approaches to immunotherapy of cancers and infectious diseases, which are in Phase 3 clinical trials in over 200 hospitals worldwide.

(3) We have also shown heat shock proteins to elicit regulatory CD4+ T cells; the mechanism of this phenomenon as well as its application to therapy of autoimmune diseases are of continuing interest to us.

(4) This laboratory has a new-found interest in neuro-immunology. We do not have much of a track record in this area, as we just published our first paper in it. Our interest is driven by the many observations that demonstrate a clear link between the nervous and the immune systems. We aim to explore those links through new phenomena and their mechanisms at the molecular, cellular and organismal levels.

Binder RJ, Srivastava P. Peptides chaperoned by heat-shock proteins are necessary and sufficient for priming CD8+ T cells. Nature Immunol., 2005, May 1, in press.

Basu S, Srivastava P. Immunological role of neuronal receptor vanilloid receptor 1 expressed on dendritic cells. Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5120-5.

Binder RJ, Srivastava PK. Essential role of CD91 in re-presentation of gp96-chaperoned peptides. Proc. Natl. Acad. Sci: USA, 101(16):6128-6133, 2004.

Chandawarkar RY, Wagh MS, Kovalchin JT, Srivastava PK. Immune modulation with high dose of heat shock protein gp96: Therapy of murine autoimmune diabetes and encephalomyelitis. Intl Immunology, 16 (4):615-624, 2004.

Basu S, Srivastava PK. Fever-like temperature induces maturation of dendritic cells through induction of hsp90. Intl Immunology, 15(9):1053-61, 2003.

Srivastava PK. Hypothesis : Controlled necrosis as a tool for immunotherapy of human cancer. Cancer Immunity, Vol. 3, pg 4, 2003.

Rivoltini L, Castelli C, Carrabba M, Mazzaferro V, Pilla L, Huber V, Coppa J, Gallino G, Scheibenbogen C, Squarcina P, Cova A, Camerini R, Lewis JJ, Srivastava PK, Parmiani G. Human Tumor-Derived Heat Shock Protein 96 Mediates In Vitro Activation and In Vivo Expansion of Melanoma and Colon Carcinoma-Specific T Cells. J. Immunology, 171(7):3467-3474, 2003.

Srivastava P. Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses. Annu Rev Immunol. 2002;20:395-425.

Binder RJ, Kumar A, Srivastava PK. Naturally formed or artificially reconstituted non-covalent ?2-macroglobulin-peptide complexes elicit CD91-dependent cellular immunity. Cancer Immunity, 2 :16, 2002.

Panjwani NN, Popova L, Srivastava PK. Heat shock proteins gp96 and hsp70 activate release of Nitric Oxide by antigen presenting cells. J. of Immunology, 168 (6), 2997-3003, 2002.

Makki A, Weidt G, Blachere N, LeFrancois L, and Srivastava PK. Abrogation of tumore protection by immunization against a dominant tumor antigen. Cancer Immunity, Vol. 2, pg. 4, 2002.

Ménoret A, Li Z, Niswonger ML, Altmeyer A, Srivastava PK. An endoplasmic reticulum protein implicated in chaperoning peptides to major histocompatibility of class I is an aminopeptidase. Journal of Biological Chemistry, 276: 33313-33318, 2001.

Somersan S, Larsson M, Fonteneau JF, Basu S, Srivastava PK, and Bhardwaj N. Primary tumor tissue lysates are enriched in heat shock proteins and induce the maturation of human dendritic cells. J. of Immunology, 167: 4844-4852, 2001.

Binder RJ, Blachere NE, Srivastava PK. Heat shock protein-chaperoned peptides but not free peptides introduced into the cytosol are presented efficiently by major histocompatibility complex I molecules. J Biol Chem. 2001 May 18;276(20):17163-71.

Srivastava PK. Immunotherapy of human cancer: lessons from mice. Nature Immunol. 2000 Nov;1(5):363-6.