About

Professor J. Scott Hale leads the Hale Laboratory at the University of Utah School of Medicine's Department of Pathology, where his research focuses on the study of T cells and their critical role in the generation of immunological memory in response to viral infections and immunization. His laboratory investigates how naïve CD4+ T cells, upon activation, proliferate and differentiate into distinct T helper cell subsets with specialized effector functions tailored to protect the host against specific pathogens. In particular, his work examines the differentiation of CD4+ T cells into Th1 cells, which secrete IFNγ and contribute to cell-mediated immunity, and follicular helper T cells (Tfh), which migrate to B cell follicles to assist germinal center B cells and promote long-lived antibody responses. Following viral clearance, these T helper cell subsets can become long-lived memory T cells capable of rapidly recalling their effector functions upon reinfection. The lab's research aims to understand the signals and mechanisms that drive the differentiation and maintenance of these functionally unique effector and memory T cell subsets, with the goal of improving protective immune responses through vaccination strategies. Professor Hale's laboratory employs various mouse models of infection and vaccination to study the fundamental mechanisms of T cell differentiation and function. Utilizing mouse knockout and conditional knockout models, his research explores how transcription factors and epigenetic regulators influence gene expression programming and the function of pathogen-specific effector and memory T cell subsets. Key projects in the lab include investigating how different infections and protein immunizations affect the lineage commitment, plasticity, and function of Tfh and non-Tfh memory cells; determining the stability and function of Tfh and Th1 memory cells following multiple infections or persistent viral infection; and studying gene expression programming mediated by DNA methylation changes that regulate memory T helper cell differentiation and maintenance. Additionally, the lab examines the role of the transcription factor Tbet in Tfh and Th1 cell function during acute and chronic viral infections. Through these studies, Professor Hale's work provides important insights into how T cells acquire and maintain specialized functions, which can be leveraged to enhance prime and boost vaccination strategies to generate long-lasting protective immunity against infectious diseases.

Research topics

• Immunology
• Biology
• Medicine
• Virology
• Genetics

Selected publications

• Guidelines for T cell nomenclature

  Nature reviews. Immunology · 2025-11-18 · 26 citations

  articleOpen access
  PublisherOA PDFDOI

• Generation of antigen-specific memory CD4 T cells by heterologous immunization enhances the magnitude of the germinal center response upon influenza infection

  PLoS Pathogens · 2024-09-16 · 9 citations

  articleOpen accessSenior author

  Current influenza vaccine strategies have yet to overcome significant obstacles, including rapid antigenic drift of seasonal influenza viruses, in generating efficacious long-term humoral immunity. Due to the necessity of germinal center formation in generating long-lived high affinity antibodies, the germinal center has increasingly become a target for the development of novel or improvement of less-efficacious vaccines. However, there remains a major gap in current influenza research to effectively target T follicular helper cells during vaccination to alter the germinal center reaction. In this study, we used a heterologous infection or immunization priming strategy to seed an antigen-specific memory CD4+ T cell pool prior to influenza infection in mice to evaluate the effect of recalled memory T follicular helper cells in increased help to influenza-specific primary B cells and enhanced generation of neutralizing antibodies. We found that heterologous priming with intranasal infection with acute lymphocytic choriomeningitis virus (LCMV) or intramuscular immunization with adjuvanted recombinant LCMV glycoprotein induced increased antigen-specific effector CD4+ T and B cellular responses following infection with a recombinant influenza strain that expresses LCMV glycoprotein. Heterologously primed mice had increased expansion of secondary Th1 and Tfh cell subsets, including increased CD4+ TRM cells in the lung. However, the early enhancement of the germinal center cellular response following influenza infection did not impact influenza-specific antibody generation or B cell repertoires compared to primary influenza infection. Overall, our study suggests that while heterologous infection or immunization priming of CD4+ T cells is able to enhance the early germinal center reaction, further studies to understand how to target the germinal center and CD4+ T cells specifically to increase long-lived antiviral humoral immunity are needed.

  PublisherDOI

• Co-formulation of the rF1V plague vaccine with depot-formulated cytokines enhances immunogenicity and efficacy to elicit protective responses against aerosol challenge in mice

  Frontiers in Immunology · 2024 · 3 citations

  • Immunology
  • Medicine
  • Virology

  This study evaluated a depot-formulated cytokine-based adjuvant to improve the efficacy of the recombinant F1V (rF1V) plague vaccine and examined the protective response following aerosol challenge in a murine model. The results of this study showed that co-formulation of the Alhydrogel-adsorbed rF1V plague fusion vaccine with the depot-formulated cytokines recombinant human interleukin 2 (rhuIL-2) and/or recombinant murine granulocyte macrophage colony-stimulating factor (rmGM-CSF) significantly enhances immunogenicity and significant protection at lower antigen doses against a lethal aerosol challenge. These results provide additional support for the co-application of the depot-formulated IL-2 and/or GM-CSF cytokines to enhance vaccine efficacy.

  PublisherOA PDFDOI

• Autoimmune CD4+ T cells fine-tune TCF1 expression to maintain function and survive persistent antigen exposure during diabetes

  Immunity · 2024-10-12 · 26 citations

  articleOpen access
  PublisherOA PDFDOI

• OCA-B/Pou2af1 is sufficient to promote CD4 ⁺ T cell memory and prospectively identifies memory precursors

  Proceedings of the National Academy of Sciences · 2024-02-22 · 10 citations

  articleOpen access

  The molecular mechanisms leading to the establishment of immunological memory are inadequately understood, limiting the development of effective vaccines and durable antitumor immune therapies. Here, we show that ectopic OCA-B expression is sufficient to improve antiviral memory recall responses, while having minimal effects on primary effector responses. At peak viral response, short-lived effector T cell populations are expanded but show increased Gadd45b and Socs2 expression, while memory precursor effector cells show increased expression of Bcl2 , Il7r, and Tcf7 on a per-cell basis. Using an OCA-B mCherry reporter mouse line, we observe high OCA-B expression in CD4 + central memory T cells. We show that early in viral infection, endogenously elevated OCA-B expression prospectively identifies memory precursor cells with increased survival capability and memory recall potential. Cumulatively, the results demonstrate that OCA-B is both necessary and sufficient to promote CD4 T cell memory in vivo and can be used to prospectively identify memory precursor cells.

  PublisherDOI

• Dnmt3a-dependent <i>de novo</i> DNA methylation enforces lineage commitment and preserves functionality of memory Th1 and Tfh cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-12-06 · 3 citations

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Following acute viral infection, naïve CD4+ T cells differentiate into T follicular helper (Tfh) and T helper 1 (Th1) cells that generate long-lived memory cells. However, it is unclear how memory Tfh and Th1 cells maintain their lineage commitment. We demonstrate that Tfh and Th1 lineages acquire distinct Dnmt3a-dependent de novo DNA methylation programs that are preserved into memory. Dnmt3a deletion impairs lineage commitment and functionality of memory Th1 and Tfh cells, resulting in aberrant Runx1 upregulation that represses germinal center Tfh cell differentiation. In contrast, transient pharmacological DNA methyltransferase inhibition during priming impairs repression of Tfh-associated genes while properly silencing Runx1 , and results in enhanced Tfh cell functionality in primary and secondary responses to viral infections. Together, these findings demonstrate that Dnmt3a-mediated epigenetic programing is required to enforce T helper lineage commitment and preserve Tfh and Th1-specific functions during the recall response to infection, and reveal novel strategies to improve long-lived adaptive immunity against infectious diseases. SUMMARY This article demonstrates that Dnmt3a-dependent epigenetic programing regulates functionality and plasticity of Th1 and Tfh memory cells. Furthermore, early pharmacological inhibition of such programing enhances GC Tfh cell differentiation, suggesting novel strategies for modulating the immune response to viral infections.

  PublisherOA PDFDOI

• Immunogen-Specific Strengths and Limitations of the Activation-Induced Marker Assay for Assessing Murine Antigen-Specific CD4+ T Cell Responses

  The Journal of Immunology · 2023-02-17 · 10 citations

  articleOpen accessSenior authorCorresponding

  The activation-induced marker (AIM) assay is a cytokine-independent technique to identify Ag-specific T cells based on the upregulated expression of activation markers after Ag restimulation. The method offers an alternative to intracellular cytokine staining in immunological studies, in which limited cytokine production makes the cell subsets of interest difficult to detect. Studies of lymphocytes in human and nonhuman primates have used the AIM assay to detect Ag-specific CD4+ and CD8+ T cells. However, there is a lack of validation of the strengths and limitations of the assay in murine (Mus musculus) models of infection and vaccination. In this study, we analyzed immune responses of TCR-transgenic CD4+ T cells, including lymphocytic choriomeningitis virus-specific SMARTA, OVA-specific OT-II, and diabetogenic BDC2.5-transgenic T cells, and measured the ability of the AIM assay to effectively identify these cells to upregulate AIM markers OX40 and CD25 following culture with cognate Ag. Our findings indicate that the AIM assay is effective for identifying the relative frequency of protein immunization-induced effector and memory CD4+ T cells, whereas the AIM assay had reduced ability to identify specific cells induced by viral infection, particularly during chronic lymphocytic choriomeningitis virus infection. Evaluation of polyclonal CD4+ T cell responses to acute viral infection demonstrated that the AIM assay can detect a proportion of both high- and low-affinity cells. Together, our findings indicate that the AIM assay can be an effective tool for relative quantification of murine Ag-specific CD4+ T cells to protein vaccination, while demonstrating its limitations during conditions of acute and chronic infection.

  PublisherOA PDFDOI

• Tet2 deletion in CD4+ T cells disrupts Th1 lineage commitment in memory cells and enhances T follicular helper cell recall responses to viral rechallenge

  Proceedings of the National Academy of Sciences · 2023-08-28 · 17 citations

  articleOpen accessSenior author

  Following viral clearance, antigen-specific CD4+ T cells contract and form a pool of distinct Th1 and Tfh memory cells that possess unique epigenetic programs, allowing them to rapidly recall their specific effector functions upon rechallenge. DNA methylation programing mediated by the methylcytosine dioxygenase Tet2 contributes to balancing Th1 and Tfh cell differentiation during acute viral infection; however, the role of Tet2 in CD4+ T cell memory formation and recall is unclear. Using adoptive transfer models of antigen-specific wild type and Tet2 knockout CD4+ T cells, we find that Tet2 is required for full commitment of CD4+ T cells to the Th1 lineage and that in the absence of Tet2, memory cells preferentially recall a Tfh like phenotype with enhanced expansion upon secondary challenge. These findings demonstrate an important role for Tet2 in enforcing lineage commitment and programing proliferation potential, and highlight the potential of targeting epigenetic programing to enhance adaptive immune responses.

  PublisherOA PDFDOI

• Effector-Phase IL-2 Signals Drive Th1 Effector and Memory Responses Dependently and Independently of TCF-1

  The Journal of Immunology · 2023-12-27 · 6 citations

  articleOpen access

  Following viral infection, CD4+ T cell differentiation is tightly regulated by cytokines and TCR signals. Although most activated CD4+ T cells express IL-2Rα after lymphocytic choriomeningtis virus infection, by day 3 postinfection, only half of activated T cells maintain expression. IL-2Rα at this time point distinguishes precursors for terminally differentiated Th1 cells (IL-2Rαhi) from precursors for Tfh cells and memory T cells (IL-2Rαlo) and is linked to strong TCR signals. In this study, we test whether TCR-dependent IL-2 links the TCR to CD4+ T cell differentiation. We employ a mixture of anti-IL-2 Abs to neutralize IL-2 throughout the primary CD4+ T cell response to lymphocytic choriomeningitis virus infection in mice or only after the establishment of lineage-committed effector cells (day 3 postinfection). We report that IL-2 signals drive the formation of Th1 precursor cells in the early stages of the immune response and sustain Th1 responses during its later stages (after day 3). Effector-stage IL-2 also shapes the composition and function of resulting CD4+ memory T cells. Although IL-2 has been shown previously to drive Th1 differentiation by reducing the activity of the transcriptional repressor TCF-1, we found that sustained IL-2 signals were still required to drive optimal Th1 differentiation even in the absence of TCF-1. Therefore, we concluded that IL-2 plays a central role throughout the effector phase in regulating the balance between Th1 and Tfh effector and memory cells via mechanisms that are both dependent and independent of its role in modulating TCF-1 activity.

  PublisherOA PDFDOI

• Generation of antigen-specific memory CD4 T cells by heterologous immunization enhances the magnitude of the germinal center response upon influenza infection

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-08-31 · 3 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Current influenza vaccine strategies have yet to overcome significant obstacles, including rapid antigenic drift of seasonal influenza viruses, in generating efficacious long-term humoral immunity. Due to the necessity of germinal center formation in generating long-lived high affinity antibodies, the germinal center has increasingly become a target for the development of novel or improvement of less-efficacious vaccines. However, there remains a major gap in current influenza research to effectively target T follicular helper cells during vaccination to alter the germinal center reaction. In this study, we used a heterologous infection or immunization priming strategy to seed an antigen-specific memory CD4+ T cell pool prior to influenza infection in mice to evaluate the effect of recalled memory T follicular helper cells in increased help to influenza-specific primary B cells and enhanced generation of neutralizing antibodies. We found that heterologous priming with intranasal infection with acute lymphocytic choriomeningitis virus (LCMV) or intramuscular immunization with adjuvanted recombinant LCMV glycoprotein induced increased antigen-specific effector CD4+ T and B cellular responses following infection with a recombinant influenza strain that expresses LCMV glycoprotein. Heterologously primed mice had increased expansion of secondary Th1 and Tfh cell subsets, including increased CD4+ T RM cells in the lung. However, the early enhancement of the germinal center cellular response following influenza infection did not impact influenza-specific antibody generation or B cell repertoires compared to primary influenza infection. Overall, our study suggests that while heterologous infection/immunization priming of CD4+ T cells is able to enhance the early germinal center reaction, further studies to understand how to target the germinal center and CD4+ T cells specifically to increase long-lived antiviral humoral immunity are needed. Author Summary T follicular helper (Tfh) cells are specialized CD4+ T cells that provide help to B cells and are required to form germinal centers within secondary lymphoid organs during an immune response. Germinal centers are necessary for generating high affinity virus-specific antibodies necessary to clear influenza infections, though current vaccines fail to generate long-lived antibodies that universally recognize different influenza strains. We used a “heterologous priming” strategy in mice using a non-influenza viral infection or viral protein subunit vaccination to form memory CD4+ Tfh cells (in previously naïve mice) that can be rapidly recalled into secondary Tfh cells following influenza infection and ideally enhance the germinal center reaction and formation of high affinity antibodies to influenza better than primary Tfh cells. Our study showed that heterologous priming induced an increase in both CD4+ T and B cells early following influenza infection, suggesting we could successfully target enhancement of the germinal center. Despite the enhancement of the early germinal center cellular response, we did not see an increase in influenza-specific antiviral antibodies. Thus, while Tfh cells are critical for the generation of high affinity antibodies, other strategies to target expansion of Tfh cells during influenza vaccination will need to be developed.

  PublisherOA PDFDOI

Recent grants

• Mechanisms of CD4 T cell help for CD8 T cells during persistent viral infection

  NIH · $110k · 2012–2014

Frequent coauthors

• Rafi Ahmed

  Emory University

  18 shared

• Pamela J. Fink

  University of Washington

  17 shared

• Matthew A. Williams

  Huntsman Cancer Institute

  12 shared

• Linda M. Sircy

  Fred Hutch Cancer Center

  11 shared

• Ben Youngblood

  St. Jude Children's Research Hospital

  11 shared

• Tamar E. Boursalian

  10 shared

• Andrew Baessler

  UPMC Hillman Cancer Center

  9 shared

• Gail L. Turk

  University of Wisconsin–Madison

  9 shared

Labs

• Scott Hale LabPI