Biology subjects

Evavold, B. D.

Publications and source records attributed to Evavold, B. D..

4 recordsLinked to original sources

bioRxiv2024

Influenza-induced alveolar macrophages protect against death by malaria-associated acute lung injury (MA-ALI)

Lower respiratory tract infections are common in malaria-endemic areas, and there is some evidence that co-infections between various bacteria/viruses and Plasmodium may affect disease prognosis. In this study, we report the novel finding that co-infection with influenza/A/X31 protects mice from death by Plasmodium berghei NK65-Edinburgh, a model of severe malarial pulmonary leak which underpins malaria-associated acute lung injury (MA-ALI) and malaria-associated acute respiratory distress (MA-ARDS). Co-infected mice exhibit equivalent parasitemia as mice with malaria only, suggesting that the survival phenotype is due to differences in immune kinetics. We demonstrated that the pulmonary leak typical of PbE is attenuated in co-infected mice without alteration in CD8 T cell activation and recruitment to the lung. Upon further examination of the immune response to influenza/A/X31 we identified a population of arginase 1-expressing alveolar macrophages that traffic to the lungs early during infection. In vitro these macrophages inhibit CD8 T cell activation and proliferation better than non-arginase expressing cells. Removal of arginase-1 expressing alveolar macrophages in vivo via administration of the antimetabolite gemcitabine removed the protective effects of influenza/A/X31co-infection on MA-ALI. This study opens a route to better understanding of how to modulate the immunopathology observed in pulmonary leak associated with severe malaria, which must be achieved to rationally design therapeutic interventions for MA-ARDS / MA-ALI.

immunology↗

bioRxiv2022

Memory in Repetitive Protein-Protein Interaction Series -- in Memory of the Late Professor Robert M. Nerem

Over the past three decades, the senior author had interacted with and been mentored by the late Professor Robert M. Nerem. In his memory, the authors summarized several observations made, ideas conceptualized, and mathematical models developed during this period for quantitatively analyzing memory effects in repetitive protein-protein interactions (PPI). Interactions between proteins in an organism coordinate its biological processes and may impact its responses to changing environment and diseases through feedback systems. Feedback systems function by using changes in the past to influence behaviors in the future, which we refer here as memory. Specifically, we consider how proteins on cell or in isolation retain information about prior interactions to impact current interactions. The micropipette, biomembrane force probe and atomic force microscopic techniques were used to repeatedly assay several PPIs. The resulting time series were analyzed by a previous and two new models to extract three memory indices of short (seconds), intermediate (minutes), and long (hours) timescales. We found that interactions of cell membrane, but not soluble, T cell receptor (TCR) with peptide-major histocompatibility complex (pMHC) exhibits short-term memory that impacts on-rate, but not off-rate of the binding kinetics. Peptide dissociation from MHC resulted in intermediate- and long-term memories in TCR-pMHC interactions. However, we observed no changes in kinetic parameters by repetitive measurements on living cells over intermediate timescale using stable pMHCs. Parameters quantifying memory effects in PPIs could provide additional information regarding biological mechanisms. The methods developed herein also provide tools for future research.

biophysics↗

bioRxiv2020

Targeting OCA-B/Pou2af1 blocks type-1 diabetes and reduces infiltration of activated, islet-reactive T cells

The transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell-specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We developed an Ocab conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell-specific OCA-B loss protected mice from spontaneous disease. Protection was associated with large reductions in islet CD8+ T cell receptor specificities associated with diabetes pathogenesis. CD4+ clones associated with diabetes were present, but associated with anergic phenotypes. The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice, but diminished in monoclonal models specific to artificial or neoantigens. Rationally-designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels, and reduced T cell infiltration and proinflammatory cytokine expression in newly-diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition. ~40-word summary statement for the online JEM table of contents and alertsKim and colleagues show that OCA-B in T cells is essential for the generation of type-1 diabetes. OCA-B loss leaves the pancreatic lymph nodes largely undisturbed, but associates autoreactive CD4+ T cells in the pancreas with anergy while deleting potentially autoreactive CD8+ T cells. SummaryKim et al. show that loss or inhibition of OCA-B in T cells protects mice from type-1 diabetes.

immunology↗

bioRxiv2018

TCR-MHC Interaction Strength Defines Trafficking and Resident Memory Status of CD8 T cells in the Brain

T cell receptor-Major histocompatibility complex (TCR-MHC) affinities span a wide range in a polyclonal T cell response, yet it is undefined how affinity shapes long-term properties of CD8 T cells during chronic infection with persistent antigen. Here, we investigate how the affinity of the TCR-MHC interaction shapes the phenotype of memory CD8 T cells in the chronically Toxoplasma gondii-infected brain. We employed CD8 T cells from three lines of transnuclear (TN) mice that harbour in their endogenous loci different T cell receptors specific for the same Toxoplasma antigenic epitope ROP7. The three TN CD8 T cell clones span a wide range of affinities to MHCI-ROP7. These three CD8 T cell clones have a distinct and fixed hierarchy in terms of effector function in response to the antigen measured as proliferation capacity, trafficking, T cell maintenance and memory formation. In particular, the T cell clone of lowest affinity does not home to the brain. The two higher affinity T cell clones show differences in establishing resident memory populations (CD103+) in the brain with the higher affinity clone persisting longer in the host during chronic infection. Transcriptional profiling of naive and activated ROP7-specific CD8 T cells revealed that Klf2 encoding a transcription factor that is known to be a negative marker for T cell trafficking is upregulated in the activated lowest affinity ROP7 clone. Our data thus suggest that TCR-MHC affinity dictates memory CD8 T cell fate at the site of infection.

immunology↗