Alok Joglekar, Ph.D.
Campus: Biomedical Science Tower, 203 Lothrop St
Pittsburgh, PA 15261
- Postdoctoral fellowship, California Institute of Technology, 2013-2019
- Ph.D., Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, 2008-2013
- MSc, Biotechnology, Institute for Bioinformatics and Biotechnology, University of Pune, India, 2003-2008
- Assistant Professor, Department of Immunology
- Core Member, Center for Systems Immunology
- Joint Faculty, Department of Computational and Systems Biology
T cells respond to threats in an antigen-specific manner using somatically rearranged T cell receptors (TCRs) that recognize short peptide antigens (or targets) presented on major histocompatibility complex (MHC) proteins. A healthy human immune system is estimated to contain an enormous number (estimated to be 106-108) of unique T cells, each with a TCR that recognizes a unique antigenic target. The TCR-peptide-MHC interaction mediated between a T cell and its target cell dictates its function, and thereby influences its role in disease. The lack of approaches for antigen discovery has limited the fundamental understanding of the antigenic landscape the overall T cell response and thereby has impeded the development of targeted therapies. Our lab has recently made significant progress in the area of T cell antigen discovery. A novel high-throughput approach developed by us has demonstrated the ability to identify the target antigen of a given T cell. We propose to use this platform to address major questions in Immunology: What is the breadth of the T cell response in a given disease? How do the antigenic landscapes of T cell responses evolve over time? And What is the fundamental mechanistic basis of antigen recognition by TCRs?
Our studies will include characterizing the antigenic targets of CD8+ T cells and regulatory T cells in anti-tumor and autoimmune T cell responses and probing the mechanistic basis of cross-reactivity of T cells between self- and pathogen-derived targets. Building upon our previous work, we will also use engineered peptide-MHC receptors for modulating T cell responses in an antigen-specific manner. Furthermore, we will address one of the central challenges in immunology: Can we predict the antigenic target of a T cell based on the amino acid sequence of its TCR? We will develop experimental and computational approaches to decipher fundamental rules governing TCR-peptide-MHC interactions and develop a framework for predicting TCR ligands. Through these studies we aim to advance our fundamental understanding of the role of T cells in protective and pathogenic immunity and design novel strategies for immunotherapy. The benefit to public health includes development of targeted and thereby safer and more efficacious approaches to treat a wide range of afflictions including autoimmune disorders, infectious diseases, and cancers.
The main goals of the laboratory are:
- Examine the shifting antigenic landscape of antitumor T cell responses by performing a systems-level analysis of the targets of T cell responses
- Determine the fundamental rules of TCR-pMHC interactions and develop computational framework for predicting T Cell Receptor ligands
- Investigate novel immunotherapies for autoimmune diseases by manipulating cell signaling pathways for desired therapeutic outcome
Joglekar AV, Leonard MT, Jeppson JD, Swift M, Li G, Wong S, Peng S, Zaretsky J, Heath Jr, Ribas A, Bethune MT, Baltimore D. “T cell antigen discovery via Signaling and Antigen presenting Bifunctional Receptors.” Nature Methods. 2019 16:191–198.
Joglekar AV, Swift M, Leonard MT, Jeppson JD, Sandoval S, Baltimore D. “T cell receptor immunotherapy drives viral evolution in humanized mice”. BioRxiv: https://doi.org/10.1101/574608
Li G, Wong S, Joglekar AV, Leonard MT, Wang J, Kim J, Cheng D, Bethune MT, Peng S, Zaretsky J, Su Y, Ribas A, Witte O, Heath JR, Baltimore D. “T cell antigen discovery via trogocytosis.” Nature Methods. 2019 16:183-190.
Kuo CY, Long JD, Campo-Fernandez B, de Oliveira S, Cooper AR, Romero Z, Hoban MD, Joglekar AV, Lill GR, Kaufman ML, Fitz-Gibbon S, Wang X, Hollis RP, Kohn DB. “Site-Specific Gene Editing of Human Hematopoietic Stem Cells for X-Linked Hyper-IgM Syndrome.” Cell Rep. 2018 May 29;23(9):2606-2616.
Joglekar AV, Liu Z, Weber JK, Ouyang Y, Jeppson J, Noh W, Lamothe-Molina PA, Chen H, Kang S, Bethune MT, Zhou R, Walker BD, Baltimore D. “T cell receptors for the HIV KK10 epitope from patients with differential immunologic control are functionally indistinguishable” Proc Natl Acad Sci U S A. 2018 Feb 20;115(8):1877-1882.
Joglekar AV, Sandoval S. “Pseudotyped lentiviral vectors: one vector, many guises”. Hum Gene Ther Methods. 2017 Dec;28(6):291-301.
Bethune MT, Joglekar AV. “Personalized T cell-mediated cancer immunotherapy: progress and challenges”. Current Opinion in Biotechnology, 48:142–152.
Hoban MD, Cost GJ, Mendel MC, Romero Z, Kaufman ML, Joglekar AV, Ho M, Lumaquin D, Gray D, Lill GR, Cooper AR, Urbinati F, Senadheera S, Zhu A, Liu P, Paschon DE, Zhang L, Rebar EJ, Wilber A, Wang X, Gregory PD, Holmes MC, Reik A, Hollis RP, Kohn DB “Correction of the sickle-cell disease mutation in human hematopoietic stem/progenitor cells” Blood. 2015 Apr 23; 125(17):2597-604.
Joglekar AV, Stein L, Ho M, Hoban MD, Hollis RP, Kohn DB “Dissecting the mechanism of histone deacetylase inhibitors to enhance the activity of zinc finger nucleases delivered by integrase-defective lentiviral vectors.” Hum Gene Ther. 2014 Jul; 25(7):599-608.
Joglekar AV, Hollis RP, Kuftinec G, Senadheera S, Chan R, Kohn DB “Integrase-defective lentiviral vectors as a delivery platform for targeted modification of adenosine deaminase locus” Mol Ther. 2013 Sep; 21(9):1705-17.
Kurrey NK, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD, Doiphode RY, Bapat SA “Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells” Stem Cells. 2009 Sep;27(9):2059-68.
- T cell antigen discovery technologies
- Understanding the targets of T cell responses
- Immunotherapy using engineered cells
- Systems and synthetic immunology