About

Professor Laura Pope Hale is a Professor of Pathology and a member of the Duke Human Vaccine Institute. Her laboratory employs cellular and molecular biology techniques to investigate mechanisms responsible for generating both normal immune responses and immune-mediated diseases. The primary focus of her research is inflammatory bowel disease (IBD), an immune-mediated disorder thought to result from an abnormal immune response of a genetically susceptible host to antigens derived from enteric bacteria. Her work aims to develop optimal treatments for IBD by gaining a detailed understanding of disease pathogenesis, including triggers of intestinal inflammation and mechanisms of inflammation-associated neoplasia. Additionally, her laboratory investigates mechanisms that determine the immunogenicity of oral antigens to develop novel adjuvants for oral vaccines, which has relevance for the pathogenesis and treatment of infectious diseases affecting the gastrointestinal tract as well as for IBD. Dr. Hale is an expert in the pathologic evaluation of colitis and immunodeficiency in both humans and mice and is board-certified in Anatomic and Clinical Pathology.

Research topics

• Biology
• Immunology
• Medicine
• Cell biology
• Genetics
• Biochemistry
• Andrology
• Pathology
• Endocrinology
• Internal medicine

Selected publications

• Author Correction: Age-related epithelial defects limit thymic function and regeneration

  Nature Immunology · 2026-03-13 · 1 citations

  articleOpen access

  mistake, the images shown as "Mouse 1, 2, 3" on the right-hand panel were mistakenly images representing regions 1-3 from one representative mouse.

  PublisherOA PDFDOI

• A porcine model of acute rejection for cardiac transplantation

  Frontiers in Cardiovascular Medicine · 2025-07-18 · 2 citations

  articleOpen access

  Ex vivo machine perfusion has been growing in utility for preserving donor organs prior to transplantation. This modality has tremendous potential for bioengineering and conditioning organs prior to transplantation using small molecule or advanced therapeutics. To safely translate potential interventions, well characterized models of disease are crucial for testing the therapeutic and possible side effects that could manifest from the interventions. Acute cellular rejection remains a significant complication in organ transplantation that affects transplant recipients with significant morbidity and mortality. This disease could potentially be mitigated with therapeutic intervention during ex vivo machine perfusion. A porcine animal model of acute rejection could be characterized in order to translate human biological processes with high fidelity. The Yucatan pig breed has been increasingly used in both biomedical research and xenotransplantation applications given its similarity to the human heart. A challenge with utilizing this pig breed for designing a model of acute rejection is its highly conserved ancestral lineage, which could make it difficult to induce acute rejection in a timely and consistent manner. We present a detailed characterization of a porcine model of acute rejection based on swine leukocyte antigen mismatching paired with a limited period of clinically relevant immunosuppression. The result is a robust and consistent protocol that results in fulminant acute rejection of an intra-abdominally transplanted heart.

  PublisherOA PDFDOI

• Coordinated changes in stromal and hematopoietic cells that define the perinatal to juvenile transition in the mouse thymus

  Cell Reports · 2025-12-01 · 2 citations

  articleOpen access

  Perinatal T cells have distinctive phenotypes and functions that may be due in part to age-associated features of stromal cells in the perinatal thymus. We identify age-associated changes in mouse thymic epithelial cells, mesenchyme, endothelium, and hematopoietic antigen-presenting cells from birth to one month of age using single-cell transcriptional profiling, flow cytometry, and imaging. Coordinated cellular and molecular changes occur at 7-14 days of age, designated "transitional ages," as thymus growth switches to homeostasis. E2F target gene expression declines, and the expression of type I interferon response genes increases across diverse cell types at transitional ages. Alterations in thymic stromal cells coincide with elevated markers of thymocyte self-reactivity and enhanced Treg suppressive phenotypes and function. The integrated results reveal coordinated remodeling of multiple stromal cell types during the perinatal to juvenile transition, which likely impacts T cell differentiation. These datasets provide a resource for the investigation of the perinatal thymus environment.

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• Insulin-like growth factor 2 as a driving force for exponential expansion and differentiation of the neonatal thymus

  Development · 2025-03-20 · 2 citations

  articleOpen access

  Like all organs, the thymus grows in size and function rapidly during development, but this growth comes to a halt after birth. However, the molecular mechanisms behind such a transition in the thymus remain obscure. Using single-cell RNA sequencing (scRNA-seq) of the murine thymic stroma, we identified that major transcriptomic changes occur in the endothelium and mesenchyme across the transition to homeostasis. Differentially expressed gene and intercellular network analyses of temporally resolved scRNA-seq data revealed fibroblast-derived insulin-like growth factor 2 (IGF2) as a candidate driving neonatal thymic expansion. We demonstrated that IGF2 activity promotes a cortical thymic epithelial cell-specific proliferation and is tightly regulated at the thymic growth transition. Bulk RNA-seq of human thymi across the transition also revealed that IGF2 drives thymic expansion, suggesting an evolutionarily conserved role. Our study highlights the role of fibroblast-derived IGF2 in promoting cortical thymic epithelial cell proliferation and differentiation, resulting in early thymic expansion that is followed by downregulation to establish homeostasis.

  PublisherOA PDFDOI

• Coordinated changes in thymic stromal and hematopoietic cells that define the perinatal to juvenile transition

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-11 · 1 citations

  preprintOpen access

  SUMMARY T cells in the perinatal thymus have distinct phenotypes and functions that may be instructed by age-specific features of the microenvironment. We evaluated molecular and cellular profiles of thymic stromal cells, including thymic epithelial cells (TECs), mesenchyme, endothelium, and hematopoietic antigen presenting cells (hAPCs), from birth through one-month of age in mice. Single-cell transcriptional profiling, flow cytometry, and immunohistochemistry revealed coordinated stromal changes accompanied by altered thymocyte differentiation at defined transitional ages during the shift from perinatal growth to juvenile homeostasis, which was mirrored in humans. These analyses link diminished IGF2 expression by mesenchymal cells with activation of the RB pathway in TECs at the transition. Moreover, a coordinated increase in type I interferon signaling in stroma across the transition is associated with altered antigen processing and presentation signatures in TECs and hAPCs. Collectively, these datasets provide a resource to interrogate thymic stroma across the perinatal to juvenile transition.

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• Whole-Thorax Irradiation Induces Persistent T Cell Clonal Dysregulation in Pediatric Rhesus Macaques

  Radiation Research · 2025-08-20

  article

  The thymus is critical for the development and selection of T cells with a diverse range of non-self-reactive antigen receptors. Both the thymus and circulating T cells can be damaged by acute exposure to ionizing radiation, leading to dose-dependent lymphopenia, a temporarily increased risk of infection that can be life-threatening, and long-term disruptions in T cell homeostasis and function. Currently, there are no biomedical countermeasures available to prevent radiation-induced T cell lymphopenia or other T cell defects caused by radiation. Therefore, preclinical models of radiation-induced thymic injury are necessary for testing countermeasures. Adult mice and non-human primates (NHP) that are subjected to whole-body or thorax irradiation are suitable models for this purpose. However, findings from these models may not directly apply to juveniles, given the significant changes in thymus size and function during childhood. To address this, we characterized the effects of 10 Gy whole-thorax irradiation on the thymus of pediatric rhesus macaque NHPs. Computed tomography (CT) assessments of thymic density and volume were used as in vivo indicators of thymic injury, but they did not correlate with the changes in thymic weight observed 19 weeks after irradiation. Histopathological staining revealed that whole-thorax irradiation caused disruption of thymic architecture, evident four months post-irradiation in some animals. Molecular analyses showed that radiation led to a decrease in thymic output, reduced diversity of T cell antigen receptors, and an over-representation of certain receptor sequences indicative of extensive clonal expansion. Overall, this work demonstrates the usefulness of the NHP whole-thorax irradiation model-commonly employed in lung radiobiology research-in studying radiation-induced thymic injury in children and in developing medical countermeasures.

  PublisherDOI

• Reconstitution of thymopoiesis via implantation of cryopreserved cultured thymus tissue into athymic recipients

  American Journal of Transplantation · 2025-11-17 · 1 citations

  articleOpen access1st authorCorresponding
  PublisherOA PDFDOI

• A TLR4-HSP70 efferocytic program in thymic macrophages sustains thymic homeostasis and T cell output

  Blood · 2025-11-03

  articleOpen access

  Abstract T cell reconstitution is essential for immune recovery after hematopoietic cell transplantation (HCT) and requires a functional thymus to generate naïve T cells. However, thymic regenerative failure remains poorly understood and lacks therapeutic strategies, leaving patients vulnerable to infections, impaired vaccine responses, and poor immune recovery. Inspired by historical reports of natural variation in thymic size across inbred mouse strains, we compared multiple inbred strains of mice. We found that C3H/HeJ (HEJ) mice, which harbor a nonfunctional Tlr4 allele, exhibit markedly reduced thymic size, impaired regeneration after injury, and persistent thymic apoptotic debris. In contrast, Tlr4-competent C3H/FeJ (FEJ) mice maintain robust thymic cellularity and regenerative potential. Crossbreeding and genetic mapping confirmed a dominant role for Tlr4 in regulating thymic size. Myeloid-specific deletion of Tlr4 in Csf1rCre+Tlr4flox mice recapitulated the HEJ phenotype, while deletion in endothelial or mesenchymal cells had no effect, indicating a macrophage-intrinsic mechanism. Mechanistically, Tlr4 signaling in thymic macrophages licensed a p65-dependent efferocytic program involving lysosomal remodeling and metabolic activation. Bulk RNA-seq of sorted thymic macrophages from Tlr4-deficient mice revealed impaired induction of genes regulating phagolysosomal fusion, lipid metabolism, and immune resolution. While ATAC-seq showed minimal changes in global chromatin accessibility, CUT&RUN profiling identified altered p65 binding at enhancers of differentially expressed genes. This suggests that Tlr4 signaling modifies transcription by directing p65 to lysosomal effector gene enhancers. Functionally, Tlr4-deficient macrophages failed to undergo efferocytic reprogramming, exhibiting impaired apoptotic cell uptake, defective acidification, and reduced lysosomal gene expression as measured by flow cytometry and immunohistochemistry. Live imaging and electron microscopy further revealed intracellular accumulation of undigested apoptotic cargo. This led to increased release of inflammatory mediators from uncleared apoptotic thymocytes, ultimately disrupting the local regenerative niche. While Tlr4 can bind to microbial products, germ-free and antibiotic-treated mice retained normal thymic size, supporting a non-microbial source of Tlr4 activation. Thus, to identify endogenous Tlr4 ligands, we engineered a Tlr4-TurboID fusion construct and performed proximity-dependent biotin labeling in the presence of apoptotic thymocytes. Mass spectrometry revealed heat shock protein 70 (HSP70) as a Tlr4-interacting protein. Stimulation of macrophages with HSP70 triggered NF-κB activation, suggesting that apoptotic cell–derived HSP70 functions as an endogenous rheostat of macrophage activity. This axis remains pharmacologically targetable, as treatment with monophosphoryl lipid A (MPLA), a clinically used TRIF-biased Tlr4 agonist, enhanced thymic cellularity, while this did not happen with non-TRIF-biased Tlr4 agonists. MPLA increased efferocytosis in thymic macrophages of UBQGFP mice and improved chromatin accessibility in macrophages at loci involved in phagosome acidification and lysosomal metabolism, leading to enhanced output of recent thymic emigrants in Rag2GFP mice. In contrast, Tlr4-deficient macrophages failed to respond to MPLA, showing no efferocytic or transcriptional activation, confirming that this therapeutic benefit requires intact Tlr4 signaling. Similarly, human apoptotic thymocytes activated TLR4 in a HEK-Blue TLR4 reporter cell line and human thymic samples had spatially organized apoptotic foci around efferocytotic macrophages in the human thymus during stress. Human thymic macrophages expressed the highest TLR4 expression of all cells by sigle cell sequencing, and CD163+LAMP1 macrophages exhibited active efferocytosis with distinct spatial characteristics in regions of apoptotic thymocyte clearance with active thymopoiesis in samples across lifespan. Together, our findings define a conserved macrophage-intrinsic Tlr4–HSP70 axis that calibrates thymic regeneration through p65-mediated efferocytic function. This apoptosis-sensing pathway sustains thymic homeostasis and adaptive lymphopoiesis and its therapeutic activation via MPLA represents a promising and translatable strategy to restore thymic function, enhance immune competence, and improve outcomes in patients undergoing cytoreduction, aging, or transplantation.

  PublisherOA PDFDOI

• Age-related epithelial defects limit thymic function and regeneration

  Nature Immunology · 2024-08-07 · 73 citations

  articleOpen access

  The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals.

  PublisherOA PDFDOI

• Comprehensive Flow Cytometric, Immunohistologic, and Molecular Assessment of Thymus Function in Rhesus Macaques

  ImmunoHorizons · 2024-07-01 · 1 citations

  articleOpen access1st authorCorresponding

  The critical importance of the thymus for generating new naive T cells that protect against novel infections and are tolerant to self-antigens has led to a recent revival of interest in monitoring thymic function in species other than humans and mice. Nonhuman primates such as rhesus macaques (Macaca mulatta) provide particularly useful animal models for translational research in immunology. In this study, we tested the performance of a 15-marker multicolor Ab panel for flow cytometric phenotyping of lymphocyte subsets directly from rhesus whole blood, with validation by thymectomy and T cell depletion. Immunohistochemical and multiplex RNA expression analysis of thymus tissue biopsies and molecular assays on PBMCs were used to further validate thymus function. Results identify Ab panels that can accurately classify rhesus naive T cells (CD3+CD45RA+CD197+ or CD3+CD28+CD95-) and recent thymic emigrants (CD8+CD28+CD95-CD103+CD197+) using just 100 µl of whole blood and commercially available fluorescent Abs. An immunohistochemical panel reactive with pan-cytokeratin (CK), CK14, CD3, Ki-67, CCL21, and TdT provides histologic evidence of thymopoiesis from formalin-fixed, paraffin-embedded thymus tissues. Identification of mRNAs characteristic of both functioning thymic epithelial cells and developing thymocytes and/or molecular detection of products of TCR gene rearrangement provide additional complementary methods to evaluate thymopoiesis, without requiring specific Abs. Combinations of multiparameter flow cytometry, immunohistochemistry, multiplex gene expression, and TCR excision circle assays can comprehensively evaluate thymus function in rhesus macaques while requiring only minimal amounts of peripheral blood or biopsied thymus tissue.

  PublisherDOI

Recent grants

• NIH Grant R21DE016404

  NIH · $385k · 2008

• NIH Grant R21AG016826

  NIH · $460k · 2001

• NIH Grant R21CA170069

  NIH · $365k · 2016

• NIH Grant R21AT002818

  NIH · $365k · 2008

• NIH Grant R21DK075522

  NIH · $423k · 2009

Frequent coauthors

• Barton F. Haynes

  Duke University

  69 shared

• M. Louise Markert

  Duke University

  63 shared

• Darell D. Bigner

  Duke University

  52 shared

• David M. Ashley

  49 shared

• Gary E. Archer

  Duke University

  42 shared

• Gregory D. Sempowski

  Duke University Hospital

  42 shared

• John H. Sampson

  Duke Medical Center

  34 shared

• Glenn Dranoff

  31 shared

Education

• MD

  Duke University School of Medicine

  1991

• PhD, Microbiology & Immunology

  Duke University

  1990