Description of Research Expertise

Research Interests
T Cell Exhaustion, Immunotherapy, T Cell Memory, Viral Immunity, Immune Oncology, Immune Health.

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
A major goal of the research the Wherry laboratory is to understand the fundamental biology of T cell exhaustion during chronic infections and cancer. Our work has defined the nature of T cell exhaustion including altered function, limited responses to antigen restimulation, high co-expression of inhibitory receptors such as PD-1, and a characteristically distinct transcriptional program. We have defined the importance of limited protective capacity of these cells during infection and cancer and have also uncovered the pathways involved in re-invigorating these cells by checkpoint blockade. We have identified subsets of exhausted T cells with different functions and reinvigoration potential and delineated the developmental relationships between these subsets. We have also found a major mechanism limiting responses of exhausted T cells. By profiling the open chromatin landscape of exhausted CD8 T cells we found that these cells were completely distinct from effector and memory CD8 T cells. Moreover, this epigenetic landscape did not change upon checkpoint blockade resulting in a reversion to exhaustion after transient benefit. These data identified exhausted T cells as a distinct immune lineage separate from effector and memory CD8 T cells. Our work has also now discovered the lineage programmer of exhausted CD8 T cells call Tox, an HMG transcription factor that induces the epigenetic changes associated with CD8 T cell exhaustion. Ongoing work continues to interrogate the mechanisms of Tox and other regulators of exhausted T cell formation, regulation and reversibility.
A second major focus in the lab is to use knowledge of fundamental immune biology, including of exhausted T cells, but also follicular helper T cells and B cells, to perform high dimensional immune profiling in human disease. We have applied these approaches to immune oncology where we first identified exhausted T cells as the major responding cell type in human cancer patients receiving PD-1 blockade treatment. We have also applied these approaches to understanding the combination of checkpoint blockade and radiation in cancer, HIV infection, human influenza virus vaccination, human immune cell migration, and pediatric respiratory infections. Our goal is to use such approaches to define the baseline, and disease associated, features of overall Immune Health and use this information to interrogate individual responses to therapeutic interventions.
Overall, our laboratory uses many high dimensional immune profiling approaches, genomics including RNA-seq, scRNA-seq, ATA-seq, scATAC-seq, other epigenetic profiling approaches, high dimensional imaging (CODEX) and rests on a strong foundation of computational biology and informatics.

Lab Rotation Projects
1) Immune regulation including checkpoint blockade during chronic viral infections and cancer
2) Transcriptional regulation of T cell differentiation
3) Immune profiling during human disease and intervention
4) Epigenetics and immune regulation
5) In vivo CRISPR screening of T cell responses
6) Immune engineering and synthetic biology to overcome or modulate T cell exhaustion.

For scheduling, administrative and departmental issues please contact
Brady Galan, Executive Assistant - brady.galan@pennmedicine.upenn.edu

For laboratory related questions, please contact
Christopher Holliday, Lab Manager - christopher.holliday@pennmedicine.upenn.edu

Lab personnel
Victor Alcalde – Research Technician
Mohammad Ali – Research Specialist
Reid Banciella – Graduate Student
Jessica Barragan – Graduate Student
Trent Campos – Undergraduate Student
Maria Cardenas – Postdoctoral Researcher
Naomi Douek – Research Technician
Victoria Fang – Postdoctoral Fellow (MD/PhD)
Benjamin Fensterheim – Postdoctoral Fellow (MD/PhD)
Audrey Gang – Undergraduate Student
Jon Ghergurovich – Postdoctoral Fellow (MD/PhD)
Josephine Giles – Senior Research Investigator
Elliot Goepfert-Waterman – Research Technician
Sophie Gray-Gaillard – Graduate Student
Chris Holliday – Lab Manager
Hua Huang – Research Specialist
Jane Huang – Postdoctoral Researcher
Wumesh Kc – Postdoctoral Fellow (MD/PhD)
Max Klapholz – Graduate Student
Jonathan Kotzin – Postdoctoral Fellow (MD/PhD)
Mathew Lee – Graduate Student
Stefan Lundh – Graduate Student
Sasikanth Manne – Research Specialist
Divij Mathew – Postdoctoral Researcher
Brittney Newby – Postdoctoral Fellow (MD/PhD)
Shin Ngiow – Postdoctoral Researcher
Mark Painter – Postdoctoral Researcher
Simone Park – Postdoctoral Researcher
Matthew Sullivan – MD/PhD Student
Joseph Tandurella – Graduate Student
Leonel Torres – Graduate Student
Van Truong – Graduate Student
Ping Wang – Postdoctoral Researcher

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.

back to top
Last updated: 03/31/2025
The Trustees of the University of Pennsylvania