About

Thomas S. Griffith earned his Ph.D. from Washington University in 1996, where he examined the cellular and molecular mechanisms of ocular immune privilege. He was a postdoctoral scientist at Immunex Corporation from 1997 to 1999, contributing to the initial characterization of TRAIL (TNF-related apoptosis-inducing ligand). In 1999, Dr. Griffith moved to the Department of Urology at the University of Iowa, where he continued evaluating TRAIL as an antitumor therapeutic. He joined the University of Minnesota Department of Urology as an associate professor in August 2011 and has since been promoted to professor. Dr. Griffith is also a member of the Masonic Cancer Center, the Center for Immunology, and the Microbiology, Immunology, and Cancer Biology Graduate Program at the University of Minnesota. His research focuses on tumor immunology and apoptosis, specifically studying the therapeutic potential of apoptotic cell death in cancer treatment. His laboratory investigates the use of TRAIL as a potent inducer of tumor cell apoptosis that is non-toxic to normal tissues, employing gene delivery systems such as recombinant adenoviral vectors to induce tumor cell death and activate systemic antitumor immunity. Additional studies explore how apoptotic cells influence immune responses using experimental models of tolerance and sepsis.

Research topics

• Biology
• Medicine
• Immunology
• Internal medicine
• Endocrinology

Selected publications

• Toll-Like Receptor 7/8 Antagonist Promotes Interleukin-10-Mediated Anti-inflammatory Therapy

  ACS Pharmacology & Translational Science · 2025-12-11

  articleOpen access

  Toll-like receptors (TLR) 7 and 8 are pattern recognition receptors expressed in immune cells, such as dendritic cells (DC) and macrophages, that respond to viral and bacterial infections. TLR7/8 activation triggers a pro-inflammatory immune cascade that leads to T cell and NK cell activation. Hence, synthetic imidazoquinoline-structured TLR7/8 agonists were developed and demonstrated as potent immunotherapy candidates for cancer and as infectious disease vaccine adjuvants. However, whether antagonizing TLR7/8 can induce the opposite effect, which is to produce anti-inflammatory cytokines and induce immunosuppressive cellular phenotypes, is a gap in our knowledge. In this study, we investigated the immunosuppressive efficacy of a novel TLR7/8 antagonist (termed "621") using cellular and animal models of inflammation. The potent TLR7/8 agonist 558 was employed as a control group to contrast the underlying immune mechanisms induced by TLR7/8 antagonist 621. Using mouse DC assays, we found that 621 was a potent inducer of the anti-inflammatory cytokine IL-10 without triggering pro-inflammatory TNF production. When administered systemically, 621-treated mice showed an increased serum IL-10 and decreased serum TNF. 621-treated mice also showed increased frequencies of regulatory T cells (Treg) and M2 macrophages when challenged with immunostimulants such as TLR4 agonist lipopolysaccharide (LPS) or the canonical TLR7/8 agonist resiquimod (RESQ). Further, 621 therapy mitigated the DSS-colitis model by reducing colon pro-inflammatory cytokines and increasing splenic Tregs. Combined, our data suggest that 621 can facilitate robust anti-inflammatory and immunosuppressive immune responses and therefore can be applied as a novel therapy for inflammatory diseases.

  PublisherOA PDFDOI

• Discovery of Highly Potent C7 Methyl Acetate Substituted Imidazoquinoline-Based TLR7 and TLR8 Agonists

  ChemRxiv · 2025-11-03

  article

  A series of highly substituted imidazoquinolines were synthesized and evaluated for Toll-like receptor (TLR) 7 and 8 activity and potency in stimulating pro-inflammatory cytokine production. The approach applies structure activity relationship data to evaluate the potentiating effects of ring substitutions to the C7-position. Our results show a clear correlation between the inclusion of a C7 methyl acetate group and TLR7 and 8 activity of substituted imidazoquinoline analogs. The most active compounds identified also contain C2 butyl and N1 aminobenzyl substitutions with several analogs displaying single digit nanomolar TLR7 agonist activity. The immunostimulatory effects of the compounds were further evaluated in vitro using human peripheral blood mononuclear cells (PBMCs) and mouse bone marrow-derived dendritic cells (BMDCs). The most potent compounds induce significant production of TNF-α, IL-1β, and IFN-γ by PBMC and expression of MHC II, CD40, and CD80 on BMDCs. A structural model of the TLR7-agonist complex is presented that shows the C7 acetate forms stabilizing H-bonding contacts with several charged amino acid sidechains near the surface of the receptor. The collective results provide strong evidence that correlates the enhanced potency of the C7 acetate analogs to recognition elements at this new site, providing insight to the design of TLR7 and TLR8 ligands.

  PublisherDOI

• A Novel Imidazoquinoline With TLR 7/8, STING, and Inflammasome Activity Demonstrates Antitumor Efficacy in Mouse Melanoma and Neu-Driven Mammary Adenocarcinoma

  Journal of Immunotherapy · 2025-08-06 · 1 citations

  article

  Activation of endosomal Toll-like receptors 7 and 8 in antigen-presenting cells typically results in the induction of type I interferons (IFN). We previously reported a series of imidazoquinolines that potently activate TLR7/8. The potency and selectivity of these compounds can be tuned via substitutions to the N1 and C2 positions of the tricycle. Furthermore, C2-alkyl substitutions that project into a hydrophobic pocket at the dimer interface of the receptor significantly affect TLR7 and TLR8 activities. In the current study, we show that these compounds induce the expression of IFN-γ, a type II IFN, in addition to the classic type I IFNs. To understand the mechanism of type II IFN induction, we utilized global proteomics to evaluate the effect of our lead TLR7/8 agonist 4-amino-1-(4-(aminomethyl)benzyl)-2-butyl-7-methoxycarbonyl-1 H -imidazo[4,5- c ]quinoline (558) on dendritic cells (DCs). These studies show 558 activated STING and inflammasome pathways, in addition to its effect on TLR7/8. Based on the multifactorial mechanism of action, we also investigated the therapeutic benefit of 558 as a single agent. The effect of 558 dosing on various immune cell populations was investigated in tumor-bearing and healthy mice. Further, the effect of 558 on tumor multiplicity and tumor burden was studied in the transgenic Balb- neu T mice, which develop neu-driven mammary adenocarcinomas. 558 reversed the tumor-induced declines in antitumor immune cells in the bone marrow and lymph nodes of tumor-bearing mice. In vivo studies showed that 558 significantly reduced the rate of tumor growth, likely due to enhanced DC activation in the lymph nodes and CD8 T cell infiltration into the tumor tissue.

  PublisherDOI

• Quantifying Nuance Within Sepsis-Associated Immune Suppression Toward Diagnostic Certainty

  Shock · 2025-10-21

  article

  Plain Language Summary Summary: Impact of sepsis on human T-cell function and outcome was assessed. In sepsis survivors, IFNγ-production in response to T-cell stimulation remains intact, while sepsis non-survivors display exaggerated IFNγ responses to TCR-independent stimuli. Plain Language SummaryThis study explored how sepsis affects T-cell function and patient outcomes. Researchers found that sepsis survivors maintain normal IFNγ production when their T-cells are stimulated, indicating intact immune function. However, those who did not survive sepsis showed excessive IFNγ responses to stimuli that do not involve T-cell receptor (TCR) activation, suggesting a dysregulated immune response. These findings highlight differences in immune function between sepsis survivors and non-survivors, which could inform future treatments and interventions for sepsis patients. Text is machine generated and may contain inaccuracies. FAQ

  PublisherDOI

• NK cells share a universal signature of memory with B and T cells in mice and humans 3891

  The Journal of Immunology · 2025-11-01

  articleOpen access

  Abstract Description NK cells, like B and T cells, acquire immune memory; however, our understanding of memory NK cells is primarily limited to specific subsets generated during CMV infection and lacks generalized memory markers. We hypothesized a universal memory signature exists across B, T, and NK cells; thus, we performed whole transcriptional profiling of B, CD4 T, CD8 T, and NK cells over the course of MCMV infection. Indeed, a shared transcriptional signature delineated naïve and memory cells across all lymphocyte populations; including CD55 (DAF, decay accelerating factor), the ectonucleotidase CD39, and the transcription factor Aiolos which were all validated by flow cytometry. As such, naïve cells are CD55hiCD39-Aioloshi and memory are any other combination thereof. The capacity of these markers to delineate memory cells extended to multiple other infectious scenarios and were recapitulated in human memory B and T cells. Single cell transcriptional analysis of human lymphocytes also demonstrated functional distinction between naïve and memory cells. To solidify this memory signature for NK cells, we performed in vitro stimulation and observed upregulation of cytolytic effectors only in memory NK cells. Notably, naïve and memory NK cells exhibit distinct localization throughout the human body. These findings establish a core signature, conserved across cell lineage and species, for identifying memory broadly and provides a foundation for designing strategies to modulate immune memory. Funding Sources NIH AI168634, AI128949, T32AI148099 Topic Categories Viral Immunology (VIR)

  PublisherOA PDFDOI

• General microbial exposure tightens infection bottlenecks to reduce the likelihood of infection and systemic dissemination 2708

  The Journal of Immunology · 2025-11-01

  articleOpen accessSenior author

  Abstract Description Microbial pathogens face a variety of barriers – or bottlenecks – during infection. The importance of bottlenecks is well-recognized, based on their ability to influence host susceptibility to pathogen colonization, paths of dissemination within individual hosts, and transmission potential between hosts. However, the impact of host mechanisms, especially those mediated by the immune system, that influence bottleneck size remains to be fully delineated. Microbially-experienced mice, generated by cohousing (CoH) with pet store mice, display resistance to Gram-negative bacteremia vs. specific pathogen-free (SPF) mice, as evidenced by reduced bacterial burden across multiple tissues within the first 24 hr after infection and increased survival. To determine how general microbial exposure impacts infection bottlenecks, we used barcoded E. coli to perform bacterial lineage tracing in vivo and quantification of infection bottlenecks. CoH mice had tighter infection bottlenecks than SPF mice, which correlated with decreased pathogen burden at 24- and 72-hr post-infection. Flow cytometric analysis of the lung and spleen found increased frequency and numbers of CD11b+Ly6G- monocytes after infection in CoH mice but decreased in SPF mice. Monocyte depletion from CoH mice prior to infection revealed these cells were essential for tightening infection bottlenecks and controlling pathogen burden. Funding Sources Supported by NIH grant GM140881, HHMI Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)

  PublisherOA PDFDOI

• Impaired vaccine-elicited humoral protection in sepsis surviving hosts 3760

  The Journal of Immunology · 2025-11-01

  articleOpen accessSenior author

  Abstract Description Sepsis, the life-threatening organ dysfunction stemming from the severe inflammatory response to systemic microbial infection, can affect humans of any age. One consequence of sepsis is the development of prolonged immunoparalysis that contributes to increased susceptibility to infection. With vaccination being an important means for protecting humans from infection throughout their lifetime, it is surprising that there has been no study performed to date assessing vaccine efficacy in sepsis survivors. We found neonatal and adult mice given an intramuscularly delivered inactivated multivalent influenza vaccine 30 days after sepsis induction had reduced total and class switched Ab titers, compared to non-septic controls. The reduced humoral response was due, in part, to impaired CD4 T cell and B cell responses to the vaccine. Reduced Ab titers were similarly seen in post-septic mice given an intranasal live-attenuated influenza vaccine. ELISpot data demonstrating reduced numbers of antibody secreting cells in the spleens of vaccinated septic mice further support the ELISA results. Moreover, mice vaccinated prior to sepsis induction also showed reduced antibody titers. Importantly, vaccinated septic mice had reduced protection to a lethal influenza challenge, demonstrated by increased mortality and viral burden in the lungs. These data collectively show how sepsis can lead to increased susceptibility to pathogens normally neutralized by vaccine-induced immunity. Funding Sources Supported by NIH/NIAID R35 GM140881; 5R01 GM139046; 1T32TR004385 Topic Categories Translational and Interventional Immunology (TI)

  PublisherOA PDFDOI

• Whole-body irradiation leads to long-term impairment in the maintenance and function of self- and non-self-epitope specific naïve CD4 T cells 3266

  The Journal of Immunology · 2025-11-01

  articleOpen access

  Abstract Description Increasing demand for nuclear power and radiotherapy has expanded new avenues for whole-body irradiation (WBI) to humans, urging the need to understand its impact on immune cells. While existing studies primarily focus on the numerical recovery of naïve T cells post-WBI, impact of WBI on naïve T cell function is less explored. Here, we used Experimental Autoimmune Encephalomyelitis (EAE) and LCMV-Arm infection models in mice to test naïve CD4 T cell function post-WBI. Mice subjected to sub-lethal WBI sustain lymphopenia after 10 days, and achieves lymphoreplete state by 40 days post WBI. Infection or immunization of lymphopenic WBI survivors led to poor protective (GP66) or pathogenic (MOG38) CD4 effector response respectively, suggesting CD4 T cell intrinsic damage by WBI. Interestingly, MOG immunization of lymphoreplete WBI survivors +/- pertussis toxin potentiated EAE disease, suggestive of WBI mediated Blood-brain barrier (BBB) impairment as a major T cell extrinsic factor contributing to this phenotype. In the infection model, this WBI mediated BBB impairment also led to an increase in total CD4 TRM, and GP66-specific CD4 T cells in the brain of mice. Overall, WBI directly impacts the number and function of both auto-reactive and virus-specific CD4 T cells, while helping them enter the BBB by changing the environment. This study is a step towards understanding the timing for medical interventions like vaccination strategies to improve T cell function in WBI survivors. Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)

  PublisherOA PDFDOI

• Determining potential immunomodulatory drug efficacy in sepsis using ELISpot

  Scientific Reports · 2025-04-18 · 6 citations

  articleOpen access

  This study evaluated the ability of ELISpot to identify potential immuno-modulatory drug therapies in sepsis. ELISpot was performed ex vivo on whole blood from septic patients and healthy controls. Innate and adaptive immunity were evaluated by production of TNF-α and IFN-γ, respectively. Drug efficacy was determined by their effects to modulate the both the number of cytokine-producing cells and amount of cytokine produced per cell. The corticosteroid dexamethasone was evaluated for its ability to down modulate TNF-α and IFN-γ production. The TLR7/8 agonist resiquimod (R848) and T cell stimulants IL-7 and anti-PD-1 mAb were tested for their ability to enhance immunity. LPS and resiquimod increased total TNF-α production in septic patients by 1,549% and 1,829%, respectively. Conversely, dexamethasone diminished the responses to LPS or resiquimod by 75% and 61%, respectively. IL-7, but not anti-PD-1 mAb markedly increased IFN-γ production in both healthy subjects (121%) and septic patients (82%). Dexamethasone also reduced anti-CD3/CD28 mAb stimulated IFN-γ production by 69%; while IL-7 ameliorated dexamethasone-induced suppression. IL-7 significantly enhanced lymphocyte function in over 90% of septic patients. ELISpot can reveal host immune response patterns and the effects of drugs to selectively down- or up-regulate patient immunity. Furthermore, the ability of ELISpot to detect the effect of specific immuno-modulatory drugs to independently regulate the innate and adaptive host response could enable precision-based immune drug therapies in sepsis.

  PublisherOA PDFDOI

• General microbial exposure establishes sustained myelopoiesis to provide enhanced innate resistance to infection 2709

  The Journal of Immunology · 2025-11-01

  articleOpen accessSenior author

  Abstract Description Bacterial infection of the bloodstream is a significant cause of morbidity and mortality worldwide. Studies with microbially experienced laboratory mice, produced by cohousing (CoH) with pet store mice, have provided insight on T cell biology not readily apparent in specific pathogen-free (SPF) mice. However, less is known about the impact of general microbial exposure on myeloid cell development and biology. Our data show the generalized microbial exposure experienced by CoH mice causes rapid (by d3), but sustained (d60), fundamental changes in early myeloid progenitor cells. CoH mice have more total bone marrow cells per femur, and an increased percentage and number of granulocyte/monocyte progenitors (GMP) within the lineage-cKit + (LK) subset, compared to SPF mice. Analysis of lineage-Sca1+cKit + (LSK) progenitors also showed a skewing toward MPP-granulocyte/monocyte (MPP-G/M) and away from MPP-lymphocyte (MPP-Ly) cells in CoH bone marrow. As such, CoH mice have an increase in CD115+ monocytes in the bone marrow and enhanced egress of Ly6ChiCD115+ monocytes from the bone marrow into the blood. CoH CD115+ monocytes have a higher mitochondrial content and metabolic activity, and show increased steady-state and LPS-induced TNF production. These features correlate with CoH mice being more resistant to systemic E. coli infection, and depletion of CD115+ monocytes abrogates this resistance. Thus, CoH mice reveal fresh perspectives on the innate immune response during bacteremia. Funding Sources Supported by NIH grants AI154527, GM140881, GM134880, AI165553 Topic Categories Hematopoiesis and Immune System Development (HEM)

  PublisherOA PDFDOI

Recent grants

• BLRD Research Career Scientist Award Application

  NIH · 2023–2027

• NIH Grant R56AI077565

  NIH · $372k · 2011

• NIH Grant R01CA109446

  NIH · $2.6M · 2015

• Using microbially-experienced mice to study the innate immune response in sepsis

  NIH · 2012–2026

• CD4 T cell dysfunction and reprogramming during sepsis

  NIH · $1.9M · 2021–2027

Frequent coauthors

• Vladimir P. Badovinac

  University of Iowa

  144 shared

• Tamara A. Kucaba

  University of Minnesota Medical Center

  94 shared

• Isaac J. Jensen

  Columbia University

  50 shared

• Britnie R. James

  University of Minnesota

  49 shared

• Katherine A. Murphy

  39 shared

• Salih Şanlıoğlu

  Akdeniz University

  34 shared

• Jayanth Panyam

  Temple University

  34 shared

• Frances V. Sjaastad

  University of Minnesota

  34 shared

Labs

• Timm-Nelson LabPI