About

Martha S. Jordan, Ph.D., is a Research Associate Professor of Pathology and Laboratory Medicine at the University of Pennsylvania and a Scientist at the Parker Institute for Cancer Immunotherapy. She also serves as Associate Vice Chair of Education in the Department of Pathology and Laboratory Medicine at the Perelman School of Medicine. Her research focuses on T cell signaling and the regulation of T cell differentiation, utilizing in vivo model systems to understand how distinct pathways and proteins influence T cell fates. Her work includes investigating the role of DNA methylation, particularly through the enzyme TET2, in T cell development and differentiation, as well as exploring mechanisms underlying T cell exhaustion in chronic viral infections and cancer. She studies how signaling proteins, such as NFkB family members and Trib1, regulate T cell activation, exhaustion, and differentiation, aiming to elucidate the molecular mechanisms involved in these processes.

Research topics

• Biology
• Cell biology
• Immunology
• Molecular biology
• Cancer research

Selected publications

• Precision CRISPR annotation of the functional enhancer landscape in primary human T cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-29

  article

  Abstract Precise modulation of T cell function through engineering the non-coding genome holds great promise for advancing next-generation immunotherapies. However, robust high-throughput approaches to annotate functional cis-regulatory elements (CRE) in human T cells remain limited. Here, we developed a simple and highly efficient CRISPR interference (CRISPRi) perturbation platform to systematically annotate CREs in human primary T cells. Using this platform, we identified novel CREs controlling PDCD1 , HAVCR2 , and TBX21 expression. Combinatorial CRE perturbations revealed synergistic CRE pairs that fine-tune PDCD1 and HAVCR2 expression, while Cas9-indel-based mutagenesis pinpointed the critical nucleotides within each enhancer that are essential for their activity. Functional experiments demonstrated that CRE-edited HAVCR2 outperformed conventional total gene knockout in enhancing CAR T cell anti-tumor efficacy. Moreover, CRE editing of PDCD1 and HAVCR2 repressed PD-1 and TIM-3 expression in human tumor-infiltrating lymphocyte CD8 T cells, highlighting regulatory role of these CREs in disease relevant exhausted T cells. Together, this approach offers a compact CRISPRi platform that enables high-throughput dissection of functionally relevant non-coding genomic regions in T cells, providing insights for mechanistic studies and precision genome engineering of advanced cellular therapies.

  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 access

  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

• TET2 regulates early and late transitions in exhausted CD8 ⁺ T-cell differentiation and limits CAR T-cell function

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-03-31

  preprintOpen access

  Abstract CD8 + T-cell exhaustion hampers disease control in cancer and chronic infections and limits efficacy of T-cell−based therapies, such as CAR T-cells. Epigenetic reprogramming of CAR T-cells by targeting TET2, a methylcytosine dioxygenase that mediates active DNA demethylation, has shown therapeutic potential; however, the role of TET2 in exhausted T-cell (T EX ) development is unclear. In CAR T-cell exhaustion models and chronic LCMV infection, TET2 drove the conversion from stem cell-like, self-renewing T EX progenitors towards terminally differentiated and effector (T EFF )-like T EX . In mouse T-cells, TET2 -deficient terminally differentiated T EX retained aspects of T EX progenitor biology, alongside decreased expression of the transcription factor TOX, suggesting that TET2 potentiates terminal exhaustion. TET2 also enforced a T EFF -like terminally differentiated CD8 + T-cell state in the early bifurcation between T EFF and T EX , indicating a broad role for TET2 in mediating the acquisition of an effector biology program that could be exploited therapeutically. Finally, we developed a clinically actionable strategy for TET2- targeted CAR T-cells, using CRISPR/Cas9 editing and site-specific adeno-associated virus transduction to simultaneously knock-in a CAR at the TRAC locus and a functional safety switch within TET2 . Disruption of TET2 with this safety switch in CAR T-cells restrained terminal T EX differentiation in vitro and enhanced anti-tumor responses in vivo . Thus, TET2 regulates pivotal fate transitions in T EX differentiation and can be targeted with a safety mechanism in CAR T-cells for improved tumor control and risk mitigation. One Sentence Summary Modulation of exhausted CD8 + T-cell differentiation by targeting TET2 improves therapeutic potential of CAR T-cells in cancer.

  PublisherOA PDFDOI

• TET2 regulates early and late transitions in exhausted CD8 ⁺ T cell differentiation and limits CAR T cell function

  Science Advances · 2024-11-13 · 27 citations

  articleOpen accessCorresponding

  CD8 + T cell exhaustion hampers control of cancer and chronic infections and limits chimeric antigen receptor (CAR) T cell efficacy. Targeting TET2 in CAR T cells provides therapeutic benefit; however, TET2’s role in exhausted T cell (T EX ) development is unclear. In chronic lymphocytic choriomeningitis virus (LCMV) infection, TET2 drove conversion from stem cell–like T EX progenitors toward terminally differentiated and effector (T EFF )–like T EX . TET2 also enforced a terminally differentiated state in the early bifurcation between T EFF and T EX , indicating broad roles for TET2 in acquisition of effector biology. To exploit the therapeutic potential of TET2, we developed clinically actionable TET2- targeted CAR T cells by disrupting TET2 via knock-in of a safety switch alongside CAR knock-in at the TRAC locus. TET2 -targeted CAR T cells exhibited restrained terminal exhaustion in vitro and enhanced antitumor responses in vivo. Thus, TET2 regulates fate transitions in T EX differentiation and can be targeted with a safety mechanism in CAR T cells for improved tumor control.

  PublisherOA PDFDOI

• Akt2 deficiency impairs Th17 differentiation, augments Th2 differentiation, and alters the peripheral response to immunization

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-06-10 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Akt1 and Akt2, isoforms of the serine threonine kinase Akt, are essential for T cell development. However, their role in peripheral T cell differentiation remains undefined. Using mice with germline deletions of either Akt1 or Akt2, we found that both isoforms are important for Th17 differentiation, although Akt2 loss had a greater impact than loss of Akt1. In contrast to defective IL-17 production, Akt2 −/− T cells exhibited enhanced IL-4 production in vitro under Th2 polarizing conditions. In vivo , Akt2 −/− mice displayed significantly diminished IL-17A and GM-CSF production following immunization with myelin oligodendrocyte glycoprotein (MOG). This dampened response was associated with further alterations in Th cell differentiation including decreased IFNγ production but preserved IL-4 production, and preferential expansion of regulatory T cells compared to non-regulatory CD4 T cells. Taken together, we identify Akt2 as an important signaling molecule in regulating peripheral CD4 T cell responses.

  PublisherOA PDFDOI

• The SWI/SNF chromatin remodeling complexes BAF and PBAF differentially regulate epigenetic transitions in exhausted CD8+ T cells

  Immunity · 2023-06-01 · 77 citations

  articleCorresponding
  PublisherDOI

• The pseudokinase Trib1 regulates the transition of exhausted T cells to a KLR+ CD8+ effector state, and its deletion improves checkpoint blockade

  Cell Reports · 2023-07-31 · 11 citations

  articleOpen accessSenior authorCorresponding

  effector state and improves checkpoint inhibitor therapy.

  PublisherOA PDFDOI

• The pseudokinase Trib1 regulates the transition of exhausted T cells to a KLR ⁺ CD8 ⁺ effector state and its deletion improves checkpoint blockade

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-02-16

  preprintOpen accessSenior authorCorresponding

  Abstract T cell exhaustion (T EX ) impairs the ability of T cells to clear chronic infection or cancer. While exhausted T cells are hypofunctional, some exhausted T cells retain effector gene signatures, a feature that is associated with expression of KLRs (killer lectin-like receptors). Although KLR + T cells may improve control of chronic antigen, the signaling molecules regulating this population are poorly understood. Using scRNA-seq, flow cytometry, RNA velocity, and scTCR-seq, we demonstrate that deleting the pseudokinase Trib1 shifts T EX towards CX3CR1 + intermediates (T INT ) with robust enrichment of KLR + CD8 + T cells (T KLR ) via clonal T cell expansion. These changes are associated with globally increased KLR gene expression throughout the exhaustion program. Further, Trib1 loss augments anti-PD-L1 blockade to improve viral clearance by expanding the T KLR population. Together, these data identify Trib1 as an important regulator of T cell exhaustion whose targeting enhances the KLR + effector state and improves the response to checkpoint inhibitor therapy.

  PublisherOA PDFDOI

• The interferon-stimulated gene RIPK1 regulates cancer cell intrinsic and extrinsic resistance to immune checkpoint blockade

  Immunity · 2022-04-01 · 91 citations

  articleOpen access
  PublisherOA PDFDOI

• MicroRNA-29a attenuates CD8 T cell exhaustion and induces memory-like CD8 T cells during chronic infection

  Proceedings of the National Academy of Sciences · 2022-04-21 · 21 citations

  articleOpen access

  CD8 T cells mediate protection against intracellular pathogens and tumors. However, persistent antigen during chronic infections or cancer leads to T cell exhaustion, suboptimal functionality, and reduced protective capacity. Despite considerable work interrogating the transcriptional regulation of exhausted CD8 T cells (TEX), the posttranscriptional control of TEX remains poorly understood. Here, we interrogated the role of microRNAs (miRs) in CD8 T cells responding to acutely resolved or chronic viral infection and identified miR-29a as a key regulator of TEX. Enforced expression of miR-29a improved CD8 T cell responses during chronic viral infection and antagonized exhaustion. miR-29a inhibited exhaustion-driving transcriptional pathways, including inflammatory and T cell receptor signaling, and regulated ribosomal biogenesis. As a result, miR-29a fostered a memory-like CD8 T cell differentiation state during chronic infection. Thus, we identify miR-29a as a key regulator of TEX and define mechanisms by which miR-29a can divert exhaustion toward a more beneficial memory-like CD8 T cell differentiation state.

  PublisherOA PDFDOI

Recent grants

• Notch Regulation of Hematopoietic Cell Fates

  NIH · $7.4M · 2000–2024

• TET2 Regulation of CD8 T cell differentiation During Chronic Viral Infection

  NIH · $443k · 2019–2022

• NIH Grant K01AR052802

  NIH · $638k · 2012

Frequent coauthors

• Gary A. Koretzky

  Weill Cornell Medicine

  138 shared

• E. John Wherry

  University of Pennsylvania

  43 shared

• Mercy Gohil

  University of Pennsylvania

  29 shared

• Josephine R. Giles

  University of Pennsylvania

  29 shared

• Andrew L. Singer

  WinnMed

  24 shared

• Jennifer E. Smith‐Garvin

  24 shared

• Jonathan S. Maltzman

  Stanford University

  23 shared

• Jiyeon S. Kim

  22 shared