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E. John Wherry

Richard and Barbara Schiffrin President's Distinguished Professor
Department: Microbiology
Graduate Group Affiliations

Contact information
421 Curie Blvd
BRB II/III Room 354
Philadelphia, PA 19104
Office: 215-746-8141
BS (Science)
Pennsylvania State University, 1993.
PhD (Immunology)
Thomas Jefferson University, 2000.
Post-Graduate Training
Post Doctoral Fellow, Department of Microbiology and Immunology, Viral Immunology, Emory University, Atlanta, GA, 2000-2004.
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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

Selected Publications

Blackburn, S.D., Shin, H., Freeman, G.J., Wherry, E.J.: Selective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade. PNAS 105(39): 15016-21, Sep 2008.

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.

Doering TA, Crawford A, Angelosanto JM, Paley MA, Wherry EJ: Defining the transcriptional networks of CD8+ T cell memory versus exhaustion. Immunity 37(6): 1130-44, 2009.

Paley MA, Kroy DC, Dolfi DV, Bikoff E, Robertson EJ, Lauer GM, Reiner SL and Wherry EJ: Key role for balancing progenitor and terminal subsets of exhausted T cells during chronic infection. Science 338(6111): 1220-5, 2012.

Crawford, A., Angelosanto, J.M., Doering, T.A., Kao, C., Wherry E.J.: Molecular and transcriptional basis of CD4+ T cell dysfunction during chronic infection. Immunity 40(2): 289-302, Feb 2014.

Kurachi M, Barnitz RA, Yosef N, Odorizzi PM, Dilorio MA, Lemieux ME, Yates K, Godec J, Klatt MG, Regev A, Wherry EJ and Haining WN.: BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells. Nature Immunology 15(4): 373-83, 2014.

Stelekati E., Shin H., Doering T.A., Dolfi D.V., Ziegler C.G., Beiting D.P., Dawson L., Liboon J., Wolski D., Ali M.A., Katsikis P.D., Shen H., Roos D.S., Haining W.N., Lauer G.M., Wherry E.J.: Bystander chronic infection negatively impacts development of CD8(+) T cell memory. Immunity 40(5): 801-13, May 2014.

Herati RS, Reuter MA, Dolfi DV, Mansfield KD, Aung H, Badwan OZ, Kurupati RK, Kannan S, Ertl H, Schmader KE, Betts MR, Canaday DH, Wherry EJ.: Circulating CXCR5+PD-1+ response predicts influenza vaccine antibody responses in young adults but not elderly adults. Journal of Immunology 193(7): 3528-37, Oct 2014.

Chang JT, Wherry EJ and Goldrath AW.: Molecular regulation of effector and memory T cell differentiation. Nature Immunology 15(12): 1104-15, DEC 2014.

Gandhi SJ, Minn A, Vonderheide RH, Wherry EJ, Hahn SM, Maity A.: Awakening the immune system with radiation: Optimal dose and fractionation. Cancer Letters March 2015.

Pauken KE, Wherry EJ.: Overcoming T cell exhaustion in infection and cancer. Trends Immunol 36(4): 265-76, April 2015.

Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, Herati RS, Mansfield KD, Patsch D, Amaravadi RK, Schuchter LM, Ishwaran H, Mick R, Pryma DA, Xu X, Feldman MD, Gangadhar TC, Hahn SM, Wherry EJ, Vonderheide RH, Minn AJ.: Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520(7547): 373-7, April 2015.

Bengsch B and Wherry EJ: The importance of cooperation: partnerless NFAT induces T cell exhaustion. Immunity 42(2): 203-5, Feb 2015.

Pauken KE, Wherry EJ.: TIGIT and CD226: tipping the balance between costimulatory and coinhibitory molecules to augment the cancer immunotherapy toolkit. Cancer Cell 26(6): 785-7, Dec 2014.

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Last updated: 11/21/2017
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