E. John Wherry

faculty photo
Richard and Barbara Schiffrin President's Distinguished Professor
Director, Institute for Immunology, University of Pennsylvania
Co-Director, Parker Institute for Cancer Immunotherapy at the University of Pennsylvania
Chair, Department of Systems Pharmacology and Translational Therapeutics
Co-Program Leader, Immunobiology Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia PA
Department: Microbiology

Contact information
421 Curie Blvd
BRB II/III Room 354
Philadelphia, PA 19104
Office: 215-746-8141
Graduate Group Affiliations
Education:
BS (Science)
Pennsylvania State University, 1993.
PhD (Immunology)
Thomas Jefferson University, 2000.
Permanent link
 

Description of Research Expertise

Research Interests
T cell exhaustion, Immunotherapy, T cell Memory, Viral Immunity, Immune Oncology. 

Key words:
T cell exhaustion, PD-1, T cell memory, Chronic infection, Cancer Immunotherapy, Checkpoint Blockade, Memory T cell differentiation, T Follicular Helper Cells.

Research Summary
One major goal of the research in Dr. Wherry's laboratory is to understand the mechanisms of T cell exhaustion during chronic infections and cancer. Our work studying exhausted CD8 T cells TEX during chronic viral infections has demonstrated that TEX lose effector functions, express multiple inhibitory receptors (e.g. PD-1, LAG-3), and fail to acquire key memory T cell properties. Using approaches including high dimensional flow cytometry, CyTOF, transcriptional and epigenetic profiling and in vivo models we are defining cellular and molecular pathways involved in T cell exhaustion. Moreover, we are defining how these findings can be used in immune oncology for cancer and chronic infections to identify biomarkers of re-invigoration of Tex. Some areas of considerable current interest for the lab include inhibitory receptors (e.g. PD-1, LAG-3), transcription factors and inflammatory pathways. Blockade of inhibitory receptors such as PD-1 (i.e. checkpoint blockade) is now a major therapeutic approach in human cancer. Ongoing studies are examining the mechanisms of these blockades in preclinical models as well as in human cancer patients and are investigating the next generation of immune targets to reverse T cell exhaustion.
A second major interest of the lab is the study of T cell memory including the biology of human T follicular helper cells (TFH). Our studies are interrogating the pathways controlling development and persistence TFH responses following human vaccination and in human chronic infections. Major efforts in these studies are to define the ontogeny of TFH in the blood and their relationship to TFH in lymphoid tissues in health and disease.
Finally, other ongoing interests in the lab include computational approaches for analysis of high dimensional cytometric, transcriptional, and epigenetic datasets, the origin of CD8 T cell memory, and other models of respiratory and intestinal viral infection.

Lab Rotation Projects
1) Regulatory mechanisms during chronic viral infections
2) Transcriptional regulation of T cell differentiation
3) Tracking immune responses during human immunotherapy
4) Epigenetics and immune regulation
5) Checkpoint blockade pathways in chronic infections.


Lab personnel
Mohamed Abdel-Hakeem - Posdoc
Sharon Adamski - Research Specialist
Mohammed Ali - Research Specialist
John Attanasio - Lab Tech
Bertram Bensch - Postdoctoral Fellow
Zeyu Chen - Graduate Student
Shin Foong Ngiow - Postdoc
Sangeeth George - Lab Tech
Josephine Giles - Postdoc
Ramin Herati - Infectious Disease Fellow
Sarah Henrickson - Pediatrics Fellow
Alex Huang - Oncology Fellow
Jonathan Johnnidis- Graduate Student
John Johnson - Graduate Student
Omar Khan - Graduate Student
Makoto Kurachi - Postdoctoral Fellow
Chi Wai Lau - Research Specialist
Sasikanth Manne - Research Specialist
Laura McLane - Research Associate
Alex Muselman - Research Tech
Kito Nzingha - Research Specialist
Robert Orlowski - HemOnc Fellow
Kunal Patel - Pulmonary Fellow
Ryan Staupe - Graduate Student
Erietta Stelekati - Postdoctoral Fellow
Vesselin Tomov – Instructor A
Laura Vella - Pediatrics Fellow
Jennifer Wu - Graduate Student

Samantha Halter - Executive Assistant

Description of Itmat Expertise

Immunology
Infectious disease
Chronic infections
Genomics and computational biology
Transcriptional profiling
Transcription factors

Selected Publications

Blackburn, S.D., Shin, H., Haining, W.N., Zou, T., Workman, C.J., Polley, A., Betts, M.R., Freeman, G.J., Vignali, D.A.A., Wherry, E.J. : Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10(1): 29-37, Jan 2009.

Paley, M.A., Kroy, D.C., Dolfi, D.V., Bikoff, E., Robertson, E.J., Lauer, G.M., Reiner, S.L, Wherry, E.J. : Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 338(6111): 1220-5, Nov 2012.

Doering, T.A., Crawfod, A., Angelosanto, J.M., Paley, M.A., Wherry, E.J.: Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity 37(6): 1130-44, Dec 2012.

Odorizzi PM, Pauken, KE, Paley MA, Sharpe A and Wherry EJ.: Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells. Journal of Experimental Medicine 212(7): 1125-37, June 2015.

Wherry E John, Kurachi Makoto: Molecular and cellular insights into T cell exhaustion. Nature reviews. Immunology 15(8): 486-99, Aug 2015.

Bengsch Bertram, Johnson Andy L, Kurachi Makoto, Odorizzi Pamela M, Pauken Kristen E, Attanasio John, Stelekati Erietta, McLane Laura M, Paley Michael A, Delgoffe Greg M, Wherry E John: Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion. Immunity 45(2): 358-73, 08 2016.

Pauken Kristen E, Sammons Morgan A, Odorizzi Pamela M, Manne Sasikanth, Godec Jernej, Khan Omar, Drake Adam M, Chen Zeyu, Sen Debattama R, Kurachi Makoto, Barnitz R Anthony, Bartman Caroline, Bengsch Bertram, Huang Alexander C, Schenkel Jason M, Vahedi Golnaz, Haining W Nicholas, Berger Shelley L, Wherry E John: Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science (New York, N.Y.) 354(6316): 1160-1165, 12 2016.

Huang Alexander C, Postow Michael A, Orlowski Robert J, Mick Rosemarie, Bengsch Bertram, Manne Sasikanth, Xu Wei, Harmon Shannon, Giles Josephine R, Wenz Brandon, Adamow Matthew, Kuk Deborah, Panageas Katherine S, Carrera Cristina, Wong Phillip, Quagliarello Felix, Wubbenhorst Bradley, D'Andrea Kurt, Pauken Kristen E, Herati Ramin S, Staupe Ryan P, Schenkel Jason M, McGettigan Suzanne, Kothari Shawn, George Sangeeth M, Vonderheide Robert H, Amaravadi Ravi K, Karakousis Giorgos C, Schuchter Lynn M, Xu Xiaowei, Nathanson Katherine L, Wolchok Jedd D, Gangadhar Tara C, Wherry E John: T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545(7652): 60-65, 05 2017.

Kurachi Makoto, Kurachi Junko, Chen Zeyu, Johnson John, Khan Omar, Bengsch Bertram, Stelekati Erietta, Attanasio John, McLane Laura M, Tomura Michio, Ueha Satoshi, Wherry E John: Optimized retroviral transduction of mouse T cells for in vivo assessment of gene function. Nature protocols 12(9): 1980-1998, Sep 2017.

Tomov Vesselin T, Palko Olesya, Lau Chi Wai, Pattekar Ajinkya, Sun Yuhang, Tacheva Ralitza, Bengsch Bertram, Manne Sasikanth, Cosma Gabriela L, Eisenlohr Laurence C, Nice Timothy J, Virgin Herbert W, Wherry E John: Differentiation and Protective Capacity of Virus-Specific CD8+ T Cells Suggest Murine Norovirus Persistence in an Immune-Privileged Enteric Niche. Immunity 47(4): 723-738.e5, Oct 2017.

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Last updated: 08/15/2018
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