About

E. John Wherry, PhD, is the Richard and Barbara Schiffrin President's Distinguished Professor at the University of Pennsylvania's Perelman School of Medicine. He serves as the Director of the Institute for Immunology & Immune Health (I3H), Co-Director of the Parker Institute for Cancer Immunotherapy, and Chair of the Department of Systems Pharmacology and Translational Therapeutics. His research focuses on understanding the fundamental biology of T cell exhaustion during chronic infections and cancer. His laboratory 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 distinct transcriptional programs. Wherry's work has identified subsets of exhausted T cells with different functions and reinvigoration potential, as well as the pathways involved in re-invigorating these cells through checkpoint blockade. His research has uncovered the epigenetic landscape of exhausted CD8 T cells, revealing that these cells are a distinct immune lineage separate from effector and memory T cells, with a major regulator called Tox. His ongoing work involves high-dimensional immune profiling in human disease, applying genomics, epigenetics, and advanced imaging techniques to understand immune responses in cancer, viral infections, and other diseases, with the goal of defining immune health and improving therapeutic interventions.

Research topics

• Immunology
• Biology
• Medicine
• Virology
• Genetics
• Internal medicine
• Pathology
• Cell biology
• Computer Science
• Computational biology
• Neuroscience
• Molecular biology
• Evolutionary biology
• Cancer research

Selected publications

• 460 LYNCH SYNDROME CARRIERS HAVE SIMILAR PREVALENCE OF IBD BUT LOWER OVERALL PREVALENCE OF AUTOIMMUNE DISEASES COMPARED TO CONTROLS

  Gastroenterology · 2026-05-01

  article
  PublisherDOI

• 460 LYNCH SYNDROME CARRIERS HAVE SIMILAR PREVALENCE OF IBD BUT LOWER OVERALL PREVALENCE OF AUTOIMMUNE DISEASES COMPARED TO CONTROLS

  Gastrointestinal Endoscopy · 2026-05-01

  article
  PublisherDOI

• In vivo reprogramming of cytotoxic effector CD8 ⁺ T cells via fractalkine-conjugated mRNA-LNP

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-30 · 1 citations

  preprintOpen access

  Abstract Selective in vivo reprogramming of cytotoxic effector CD8 + T (T eff ) cells holds tremendous promise as a therapeutic tool but has not yet been accomplished. Here, we demonstrate that fractalkine-conjugated mRNA lipid nanoparticles (mRNA-LNP) can specifically target and deliver mRNA to CX3CR1 + T eff cells in vitro and in vivo. In mice, fractalkine-conjugated LNP target up to 90% of blood and splenic T eff cells, and delivery of IL-2-encoding mRNA to T eff cells enables robust exogenous IL-2 secretion. In rhesus macaques, fractalkine-conjugated mRNA-LNP target up to ∼100% of peripheral blood T eff cells and delivery of CD62L-mRNA enables transient CD62L expression. Collectively, these data demonstrate the potential of natural receptor ligand-based targeting of mRNA-LNP for effective and efficient transient in vivo modification of T eff cells.

  PublisherOA PDFDOI

• The transcription factor BATF pioneers the differentiation program of effector CD8+ T cells through the interaction with IRF4

  Cell Reports · 2025-08-01 · 3 citations

  articleOpen access

  T cell (CTL) differentiation. Here, we demonstrated that BATF controls epigenomic and transcriptomic reprogramming of CTLs at the early stages of acute viral infection, thereby promoting effector CTL differentiation. Loss of BATF drastically perturbed gene expression, chromatin accessibility, and binding of key transcription factors. The BATF-interferon regulatory factor 4 (IRF4) interaction was essential for BATF-mediated effector differentiation, as the BATF mutant lacking this interaction failed to induce proper chromatin remodeling and proliferation of antigen-specific CTLs. Notably, IRF4 binding thoroughly depended on BATF, whereas BATF retained binding capacity even in IRF4-deficient CTLs. Furthermore, BATF initiated chromatin remodeling without IRF4; however, subsequent dynamic epigenomic reorganization required IRF4. These findings suggest that BATF serves as a "pioneer transcription factor" spearheading chromatin reorganization upon antigen encounter. This fundamental role is followed by further rearrangement of epigenomic and transcriptomic landscapes through the cooperation with IRF4.

  PublisherOA PDFDOI

• Divergent ontogeny of Tissue Resident Memory and Tissue Resident Exhausted CD8 ⁺ T cells underlies distinct functional potential

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-11 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Persistent antigen stimulation promotes differentiation of exhausted CD8 + T (T EX ) cells. T EX cells are distinct from circulating memory T (T CIRCM ) cells but share many features with tissue-resident memory (T RM ) cells established following infection resolution. CD8 + T cells co-expressing residency- and exhaustion-associated molecules in chronic diseases often correlate with clinical outcomes. However, the relationship between these cells and conventional T RM or T EX cells remains unclear. Here, we show that chronic antigen stimulation drives development of tissue-resident T EX (TR-T EX ) cells that are ontologically and functionally distinct from T RM cells generated after antigen clearance. TR-T EX phenotypically resembled T RM cells but were regulated by distinct transcriptional networks and were uniquely dependent on Tox for residency programming. Although T EX progenitor cells acquired residency features upon entering chronically infected tissues, they failed to generate conventional T RM cells after antigen withdrawal. Conversely, T RM cells were able to differentiate into T EX cells during chronic antigen stimulation. Deriving cell-state specific transcriptional signatures revealed a selective association of TR-T EX cells with patient responses to immune checkpoint blockade, and only TR-T EX but not T RM cells responded to PD-1 pathway inhibition in vivo. These data suggest that TR-T EX and T RM cells are developmentally distinct cell types that share a tissue-residency program but have distinct roles in disease control.

  PublisherDOI

• Thrombospondin-1–CD47 signaling contributes to the development of T cell exhaustion in cancer

  Nature Immunology · 2025-11-17 · 4 citations

  article
  PublisherDOI

• The MMTV envelope glycoprotein promotes the survival and function of CD8 T cells during chronic viral infection and cancer via ITAM-dependent signaling 3439

  The Journal of Immunology · 2025-11-01

  articleOpen accessSenior author

  Abstract Description Transposable elements (TEs) comprise ∼50% of the genome, yet their contributions to normal physiology beyond embryonic development are poorly understood. We hypothesized that TEs may regulate developmental processes in CD8 T cell differentiation. Here we identify an envelope glycoprotein (env) encoded by the murine mammary tumor virus MMTV that promotes the survival and function of exhausted T cells (TEX) via ITAM-dependent signaling. Analysis of TE expression across CD8 T cells revealed that endogenous MMTV is upregulated upon TEX differentiation. MMTV knockdown depletes TEX precursor cells early in LCMV clone 13 infection. Single-cell RNA analysis of MMTV knockdown cells suggested a role for MMTV preceding the early bifurcation of TCF1+ TEX precursor cells and Tim3+ effector-like cells. Accordingly, the MMTV env is co-expressed with costimulatory/inhibitory receptors within the first days of LCMV infection and also in B16OVA melanoma tumors. Overexpression of the MMTV env in OT1 T cells enhances control of B16OVA in vivo. Mutation of the MMTV env ITAM abrogates the env-dependent benefit on tumor control. Altogether our data suggest that the MMTV env ITAM promotes TEX survival and differentiation. These studies reveal an unexpected role for a TE-encoded protein in CD8 T cells and highlight one way that mammalian genomes have coopted physiological functions for endogenous retroviruses. Moreover, this work suggests a potential to exploit this ITAM signal for therapeutic gain. Funding Sources This work was supported by the Parker Institute for Cancer Immunotherapy and the Mark Foundation for Cancer Research. Topic Categories Viral Immunology (VIR)

  PublisherOA PDFDOI

• 245 Synthetic pathway activators (SPA) enhance CAR-T activity against solid tumors by reducing T cell exhaustion and increasing functional persistence in preclinical studies

  Regular and Young Investigator Award Abstracts · 2025-11-01

  articleOpen access
  PublisherOA PDFDOI

• DDDR-63. Immune remodeling in CSF and tumor predicts response to CAR T therapy in glioblastoma

  Neuro-Oncology · 2025-11-01

  articleOpen access

  Abstract Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults. We previously reported results from a phase I clinical trial demonstrating that intracerebroventricular delivery of bivalent CAR T cells, targeting EGFR (epitope 806) and IL13Rα2, led to tumor size reductions in patients with recurrent, multifocal GBM. Despite these promising results, most patients experienced tumor relapse following initial regression. To uncover mechanisms underlying response and resistance, we performed single-cell analysis of longitudinal cerebrospinal fluid (CSF) collected at Days 0, 7, and 21 from eight patients, along with matched pre- and post-treatment tumor tissue (n = 6, three patients) and infusion products (n = 4). Immune dynamics suggest that treatment efficacy is not solely driven by CAR T cells but may equally depend on recruitment and activation of the endogenous immune system. Post-infusion, CSF-circulating CAR T cells showed increased cytotoxicity and exhaustion-related programs, suggesting target engagement. Notably, CAR T infusion drove rapid expansion and activation of endogenous immune cells, including natural killer (NK) and regulatory T cells (Tregs). NK cells increased in proportion and transitioned toward a CD56dimCD16+ cytotoxic phenotype. This NK activation was significantly associated with prolonged progression-free survival. Conversely, Tregs expanded clonally in both CSF and tumor tissue and showed increased immunosuppressive interactions, including CTLA4 and Galectin-9-based signaling, which were enriched in non-responders. Treg expansion and reduced clonal entropy negatively correlated with radiographic response. Post-treatment tumor tissues showed decreased EGFR expression and reduced immunosuppressive myeloid phenotypes, suggesting a local impact of the treatment. Rather than functioning in isolation, CAR T cells act as immune catalysts – reshaping the CSF milieu by activating cytotoxic NK cells while simultaneously triggering Treg expansion. These opposing dynamics reveal actionable points of intervention: disrupting early Treg–myeloid signaling or pre-arming with NK-supportive cues could shift the balance toward more durable tumor control.

  PublisherOA PDFDOI

• Multi-omic profiling reveals age-related immune dynamics in healthy adults

  Nature · 2025-10-29 · 33 citations

  articleOpen access

  The generation and maintenance of immunity is a dynamic process that is dependent on age1–3. Here, to better understand its progression, we profiled peripheral immunity in more than 300 healthy adults (25 to 90 years of age) using single-cell RNA sequencing, proteomics and flow cytometry, following 96 adults longitudinally across 2 years with seasonal influenza vaccination. The resulting resource generated a single-cell RNA-sequencing dataset of more than 16 million peripheral blood mononuclear cells with 71 immune cell subsets from our Human Immune Health Atlas and enabled us to interrogate how immune cell composition and states shift with age, chronic viral infection and vaccination. From these data, we demonstrate robust, non-linear transcriptional reprogramming in T cell subsets with age that is not driven by systemic inflammation or chronic cytomegalovirus infection. This age-related reprogramming led to a functional T helper 2 (TH2) cell bias in memory T cells that is linked to dysregulated B cell responses against highly boosted antigens in influenza vaccines. Collectively, this study reveals unique features of the immune ageing process that occur prior to advanced age and provides novel targets for age-related immune modulation. We provide interactive tools for exploring this extensive human immune health resource at https://apps.allenimmunology.org/aifi/insights/dynamics-imm-health-age/ . This multi-omic longitudinal analysis of the healthy human peripheral immune system constructs the Human Immune Health Atlas and assembles data on immune cell composition and state changes with age, including responses to cytomegalovirus infection and influenza vaccination.

  PublisherOA PDFDOI

Recent grants

• Core A - Administrative Core

  NIH · $50.6M · 2015–2030

• NIH Grant R21AI077098

  NIH · $427k · 2009

• NIH Grant R21AI117718

  NIH · $440k · 2017

• Radiation and checkpoint blockade for cancer immune therapy

  NIH · $18.3M · 2017–2024

• NIH Grant R21AI115977

  NIH · $351k · 2017

Frequent coauthors

• Josephine R. Giles

  University of Pennsylvania

  422 shared

• Divij Mathew

  University of Pennsylvania

  306 shared

• Amy E. Baxter

  California University of Pennsylvania

  276 shared

• Alexander C. Huang

  University of Pennsylvania

  275 shared

• Sasikanth Manne

  University of Pennsylvania

  261 shared

• Allison R. Greenplate

  Translational Therapeutics (United States)

  238 shared

• Cécile Alanio

  236 shared

• Laura A. Vella

  Children's Hospital of Philadelphia

  205 shared

Education

• B.S.

  Pennsylvania State University

  1993

• Ph.D., Immunology

  Thomas Jefferson University

  2000