Brian Evavold
· Professor, Vice Chair of ResearchVerifiedUniversity of Utah · Microbiology & Immunology
Active 1986–2026
About
Brian D. Evavold, PhD, is the Chief of the Division of Microbiology and Immunology and holds the George J. Weber Presidential Endowed Chair in Immunology at the University of Utah. He is a Professor and Chief of the Division of Microbiology and Immunology in the Department of Pathology. His research centers on understanding how antigen recognition by T cells determines cell phenotype, fate, and the outcome of the adaptive immune response. By elucidating the mechanisms driving T cell activation, his work provides novel insights into the basis of autoimmune diseases and effective immune responses to infections. The Evavold Lab employs novel and sensitive techniques such as the Micropipette assay to determine single bond T Cell Receptor (TCR) affinity for peptide-MHC complexes in T cell subsets, and the Biomembrane Force Probe to analyze TCR:pMHC bond lifetimes under force. These approaches together offer a clearer picture of T cell interactions with antigens associated with self and pathogens.
Research topics
- Immunology
- Biology
- Cell biology
- Chemistry
- Computational biology
- Medicine
- Biochemistry
- Biophysics
- Combinatorics
- Mathematics
- Genetics
- Cancer research
- Internal medicine
Selected publications
Overcoming T cell tolerance to tumor self-antigens through catch-bond engineering
Science · 2026-03-19 · 1 citations
articleOpen accessT cells are often weakly responsive to tumor self-antigens because of central tolerance, constraining their ability to eliminate tumors. We exploited mechanical force to engineer a weakly reactive T cell receptor (TCR) specific for a nonmutated tumor-associated antigen (TAA), prostatic acid phosphatase (PAP). We identified a catch-bonding "hotspot" whose mutation enhanced T cell activity by increasing TCR-pMHC (peptide-major histocompatibility complex) bond lifetime while preserving physiological affinities and antigen fine specificities. T cells expressing these engineered TCRs showed vastly superior expansion in the tumor, effector phenotypes, and tumor elimination. Crystal structures and molecular dynamics simulations revealed a single amino acid mutation at the catch-bond hotspot primes the TCR for peptide interaction through water reorganization at the TCR-pMHC interface. Catch-bond engineering is a viable biophysically based strategy for transforming tolerized antitumor T cells into potent TCR-T cell therapy killers.
Journal for ImmunoTherapy of Cancer · 2025-04-01 · 4 citations
articleOpen accessBackground The presence of activated CD8 T cells in the tumor microenvironment is correlated with an effective immune response to immune checkpoint inhibitor (ICI) therapy. However, ICI predominantly targets high-affinity T cells, which may be less abundant in tumors with few neoantigens. Targeting the intracellular phosphatase Src homology region 2 domain-containing phosphatase-1 (Shp-1) in combination with ICI lowers the T cell activation threshold and enhances the ability of low-affinity T cells to mount a productive antitumor response. Methods In this study, we sought to determine whether temporal inhibition of Shp-1 during active tumor growth could rescue the activity of low-affinity T cells specific for endogenous self-antigens. To address this question, we implanted Yale University Mouse Melanoma (YUMM) tumor cell lines into WT mice and, on tumor establishment, administered an inhibitor of Shp-1 (TPI-1) with or without ICI treatment. We analyzed treatment-dependent changes in the immune infiltrate in the tumor via flow cytometry, major histocompatibility complex (MHC) tetramer-mediated detection of tyrosinase-related protein 2 (TRP-2) 180–188 -specific T cells and a micropipette-based two-dimensional affinity assay to measure the T cell receptor (TCR) affinity. Results Administration of ICI and a Shp-1 inhibitor to mice with established YUMM tumors, but neither agent alone, resulted in a significant delay in tumor growth and an increased frequency of CD8 tumor-infiltrating T cells with enhanced effector and reduced exhaustion characteristics. In particular, combined treatment increased the frequency of CD8 T cells specific for the MHC Class I-restricted tumor self-antigen TRP-2 180–188 . We found that the increase in effector T cells was almost entirely due to an increase in T cells with very low TCR affinity. Conclusions We conclude that approaches for altering TCR signaling threshold are effective in enhancing the antitumor response of low-affinity T cells specific for endogenous self-antigens in settings of ICI resistance and/or where neoantigens are not available to drive antitumor responses.
The Journal of Immunology · 2025-11-01
articleOpen accessSenior authorAbstract Description T follicular helper cells expand during immune challenge to provide T cell help for B cell responses, but it is unclear if there is a functional difference in Tfh with low or high-affinity TCRs in forming these responses. We used a micropipette assay to quantify the affinity of TCRs reactive to the lymphocytic choriomeningitis virus (LCMV) glycoprotein 66 (gp66) epitope on Tfh in three infection models: murine polyomavirus and Plasmodium yoelii, both engineered to express gp66, and LCMV. Our data demonstrate that, relative to native gp66 in LCMV infection and when expressed as a surrogate epitope on polyomavirus, P. yoeliigp66 infection expands Tfh with uniformly low affinity TCRs reactive to gp66. LCMV and polyomagp66 expanded Tfh harboring TCRs with a range of affinities. To extend our findings to an endogenous Plasmodium antigen, we quantified the affinity of TCRs on Tfh reactive to the PbTII endogenous epitope of Plasmodium heat shock protein 90. In results similar to those with gp66-reactive Tfh, we found that P. yoelii exclusively expands Tfh with low affinity PbTII specific TCRs. Again, this was Plasmodium specific as murine polyomaPbTII engineered to express the PbTII epitope expanded both high and low affinity PbTII-reactive TCRs. Collectively, this data shows that affinity of TCRs on Tfh is likely pathogen-driven as opposed to epitope-driven. This could have important implications for how Tfh affinity affects memory responses for vaccine design. Funding Sources Supported by NIH 5R01AI167422-03 Topic Categories Vaccines and Immunotherapy (VAC)
The Journal of Immunology · 2025-11-01
articleOpen accessAbstract Description Despite the presence of anti-malarial treatments, cerebral malaria persists as one of the most lethal malaria complications. CD8 T cells mediate the development of experimental cerebral malaria (ECM), which is characterized by breakdown of the blood-brain barrier (BBB). During a Plasmodium infection, CD8 T cells recognize different Plasmodium epitopes and expand, leading to polyclonal populations with T cell receptors (TCRs) of different reactivity and affinity. Generally, T cells harboring high affinity TCRs are believed to dominate any polyclonal T cell response and to be the most potent cells during an immune response. We have made the paradigm-shifting discovery that pathogenicPlasmodium-reactive CD8 T cells with low affinity TCRs dominate the CD8 T cell response during ECM. In adoptive transfer experiments, high affinity CD8 T cells are unable to drive BBB dysfunction to the same extent as low affinity cells. We have found that high and low affinity Plasmodium-reactive CD8 T cells display different phenotypes. High affinity CD8 T cells might be dysfunctional or undergoing apoptosis, consistent with their inability to mediate BBB breakdown. TCR affinity can impact functional outcome by inducing a different bond lifetime under force. We have identified TCRs specific for the Plasmodium GAP50 epitope and transfected these TCRs into 58TCR-ve cells. High affinity GAP50-specific TCRs induced longer bond lifetimes under force compared to low affinity GAP50-specific TCRs. Funding Sources NIH 5R01AI167422-04 Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)
Frontiers in Immunology · 2025-08-13
articleOpen accessBackground Bispecific killer engagers (BiKEs), which harness natural killer cells to deplete target cells, have garnered success in ablating tumor cells but have not been well explored in eliminating primary cells, such as effector cells in autoimmune diseases. Previously, we reported a BiKE that targeted human lymphocytes expressing programmed death-1 (PD-1). The BiKE was shown to promote NK cell-mediated depletion of PD-1+ cells in vitro. Here, we posited that a mouse-specific PD-1 BiKE could be used as a tool to deplete PD-1 + cells in vivo . Methods PD-1 BiKE was designed and produced in an IgG-like format. The BiKE was characterized for its functional binding, ability to facilitate NK cell-PD-1 + cell-cell interactions, and depletion of PD-1 + cells using several in vitro assays. The BiKE was then evaluated for its ability to deplete PD-1 + T cells in vivo using an EL4 tumor model, and the EAE model. Results PD-1 BiKE demonstrated selective binding to PD-1 + T cells encompassing both a cell line (EL4) and primary cells. PD-1 BiKE simultaneously engaged its two targets, PD-1 + and NK cells, and mediated a 63% increase in cell-cell interactions between the two targets. In co-cultures of primary PD-1 + T cells and NK cells, the BiKE reduced the number of T cells by 28%. Importantly, PD-1 BiKE did not reduce PD-1 - T cells when co-cultured with NK cells. In vivo , PD-1 BiKE reduced the fraction of inoculated EL4 cells by ~53%. In EAE mice, PD-1 BiKE reduced the average number of primary PD-1 + T cells by 56% and 65% in the spinal cords and brains, respectively. Beyond the IgG-like BiKE, two non-IgG-like BiKEs were also designed and generated and demonstrated strong but distinct binding to PD-1 and CD16. Conclusions The IgG-like PD-1 BiKE bound to both cellular targets, CD16 and PD-1, and was able to deplete primary PD-1 + T lymphocytes in the EAE model. Altogether, the work showcases the effectiveness of using BiKEs to deplete non-malignant cells.
Bond lifetime predicts CD4 T cell effector and memory potential 3626
The Journal of Immunology · 2025-11-01
articleOpen accessSenior authorAbstract Description Recognition of antigen and TCR signal strength is a critical step required for T cell survival, expansion, development of effector function and transition towards memory. To better understand T cell kinetic parameters impacting effector and memory bias, we utilized a panel of cloned TCRs specific for the immunodominant CD4 GP61-80 epitope of lymphocytic choriomeningitis virus (LCMV) that we previously show to favor either effector or memory fates. We analyzed the 2D affinity of 4 effector (effector-biased) and 4 memory (memory-biased) clones. All were tetramer positive and of high affinity; However, at the clonal level, affinity did not correlate with the effector or memory outcomes. Recent data on T cell responses to antigen have demonstrated the importance of bond lifetime between TCRs and antigen as they occur under applied cellular forces. After single molecule analysis between TCR and gp66:MHC antigen for 3 effector and 3 memory biased clones, effector fated cells demonstrated significantly longer bond lifetimes than memory fated clones. These data correlate with surrogate markers of TCR signal strength such as ZAP70 phosphorylation and CD25 expression. Our data identify bond lifetime between TCR and antigen as the dominant determining factor of CD4 cell effector versus memory fate during infection. Funding Sources Supported by NIH 5R01AI172253-02 Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)
iScience · 2025-10-04 · 1 citations
articleOpen accessCAR Tregs as a unique therapy with both targeted suppression and tissue repair potential.
The Journal of Immunology · 2025-11-01
articleOpen accessSenior authorAbstract Description In demyelinating disease, Tregs with the most effective suppressive capacity are self-antigen specific; however, it is unclear how the parameters of self-antigen stimulation (affinity, force, and bond lifetime) modulate suppressive potency. A critical unmet need limiting these studies is the ability to isolate antigen specific Tregs without prior knowledge of TCR reactivity. Here, we utilize the well-described myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide driven experimental autoimmune encephalomyelitis (EAE) in B6 mice and have identified GARP and CTLA4 as markers that predict Treg antigen reactivity. In this system, we show that tetramer staining in the spleen is increased in enriched GARP+ CTL4+ Tregs (30%) compared to bulk Tregs (10%). We found that GARP+ CTLA4+ Tregs are more potent antigen specific suppressors by in vitro suppression assay using 2D2 responders stimulated with MOG. We compared bond lifetime and found that peak bond lifetime shifted to higher force in CTLA4+ GARP+ Tregs. We hypothesized that trogocytosis may be a force dependent mechanism of suppression by removal of self-antigen and we found that CTLA4+ GARP+ Tregs pulled more MOG loaded MHCII from the surface of antigen presenting cells than CTLA4- Tregs. This research uncovers an understanding of surface markers that will identify potently suppressive antigen specific Tregs, which will allow the design of therapeutic strategies for Tregs in autoimmune conditions. Funding Sources NIH 5R01AI169835-03 NIH 5T32NS115664-03 Topic Categories Therapeutic Approaches to Autoimmunity (THER)
Cancer Research · 2025-04-25
articleAbstract The presence of activated CD8 T cells in the tumor microenvironment (TME) is correlated with an effective immune response to immune checkpoint inhibitor (ICI) therapy. However, ICI predominately targets high affinity T cells, which are exhaustion-prone and may be less abundant in tumors with few neoantigens. Low affinity T cells are abundant during many anti-tumor responses, and there is a need to better understand their contribution to the ICI-induced response and to determine the mechanisms controlling their activation. Targeting the intracellular phosphatase Src homology region 2 domain-containing phosphatase-1, Shp-1 (PTPN6), in combination with ICI lowers the T cell activation threshold and enhances the ability of low affinity T cells to mount a productive anti-tumor response. In this study, we sought to determine whether temporal inhibition of Shp-1 during active tumor growth could rescue the activity of low affinity T cells specific for endogenous self-antigens. To address this question, we implanted Yale University Mouse Melanoma (YUMM) tumor cell lines into WT mice, as the resulting tumors are ICI-resistant and lack abundant neo-antigens. Administration of ICI and a Shp-1 inhibitor to mice with established YUMM tumors, but neither agent alone, resulted in a significant delay in tumor growth and an increased frequency of CD8 tumor-infiltrating T cells with enhanced effector (PD-1+ Gzb+ Tbet+) and reduced exhaustion characteristics (2b4+ PD-1+). In particular, combined treatment increased the frequency of CD8 T cells specific for the MHC Class I-restricted tumor self-antigen TRP-2180-188. We utilized a micropipette-based 2D affinity assay to measure the T cell receptor (TCR) affinity of TRP-2-specific T cells in the tumor following treatment. We found that the increase in effector T cells was almost entirely due to an increase in T cells with very low TCR affinity. We conclude that approaches for altering TCR signaling threshold are effective in enhancing the anti-tumor response of low affinity T cells specific for endogenous self-antigens in settings of ICI resistance and/or where neo-antigens are not available to drive anti-tumor responses. Citation Format: Joseph G. Matous, Andrew G. Ramstead, Krystal R. Charley, Elizabeth M. Kolawale, Jacob N. Kisiolek, Brian D. Evavold, Matthew A. Williams. Shp-1 regulates the activity of low affinity T cells specific to endogenous self-antigen during melanoma tumor growth and drives resistance to immune checkpoint inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB126.
The Journal of Immunology · 2025-11-01
articleOpen accessAbstract Description Severe cerebral and pulmonary vascular damage by CD8 T cells remains a major challenge in malaria, which kills >600,000 people annually. Coinfections can significantly alter disease progression by changing the immune kinetics. Our objective was to investigate influenza coinfection, which is highly understudied in malaria. We infected C57BL/6J mice with Plasmodium berghei NK65-Edinburgh (PbE), which causes fatal pulmonary vascular leak within 6-10 days, and a sub-lethal dose of Influenza/A/X31. Surprisingly, coinfection significantly prolonged survival (20.8 vs. 9.0 days). Despite maintaining equal parasitemia as the malaria-only group, the coinfected group failed to develop the same lung pathology. We profiled the anti-influenza immune response by flow cytometry and identified an alveolar macrophage (AM) subset expressing inhibitory markers such as Arg1, iNOS, and PD-L1. This population is not induced by PR8, which also does not provide a protective phenotype during Plasmodium coinfection. In vitro suppression assays demonstrated that these AMs dampen CD8 activation and proliferation in a contact-dependent manner. Gemcitabine depletion of AMs showed that they are required for protection. These findings reveal an unprecedented coinfection dynamic where influenza-induced AMs modulate the anti-malarial response to prevent immunopathology. Ongoing work is exploring alternate strategies to induce these protective AMs, offering new potential treatments in malarial pulmonary injury. Funding Sources Supported by NIH F31HL172638-01, NIH T32AI138945-06A1, NIH R21AI185994. Topic Categories Viral Immunology (VIR)
Recent grants
NIH · $4.4M · 2015
2D affinity and frequency of antigen specific Tregs
NIH · $1.9M · 2014–2019
CD8 T cell antigen recognition during chronic infection
NIH · $3.3M · 2020–2026
NIH · $1.1M · 2009
NIH · $1.4M · 2014
Frequent coauthors
- 41 shared
Elizabeth Motunrayo Kolawole
University of Utah
- 27 shared
Lori Blanchfield
Benaroya Research Institute
- 24 shared
Cheng Zhu
The Wallace H. Coulter Department of Biomedical Engineering
- 21 shared
Baoyu Liu
Guangdong University of Technology
- 19 shared
Lindsay J. Edwards
Age UK
- 18 shared
Ryan J. Martinez
University of Minnesota
- 16 shared
Alessandro Sette
La Jolla Institute for Immunology
- 16 shared
Philippe Kourilsky
Collège de France
Labs
Awards & honors
- George J. Weber Presidential Endowed Chair in Immunology
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