Publications by authors named "Heidi J Elsaesser"

9 Publications

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A network of immune and microbial modifications underlies viral persistence in the gastrointestinal tract.

J Exp Med 2020 12;217(12)

Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.

Many pathogens subvert intestinal immunity to persist within the gastrointestinal tract (GIT); yet, the underlying mechanisms that enable sanctuary specifically in this reservoir are unclear. Using mass cytometry and network analysis, we demonstrate that chronic LCMV infection of the GIT leads to dysregulated microbial composition, a cascade of metabolic alterations, increased susceptibility to GI disease, and a system-wide recalibration of immune composition that defines viral persistence. Chronic infection led to outgrowth of activated Tbet-expressing T reg cell populations unique to the GIT and the rapid erosion of pathogen-specific CD8 tissue-resident memory T cells. Mechanistically, T reg cells and coinhibitory receptors maintained long-term viral sanctuary within the GIT, and their targeting reactivated T cells and eliminated this viral reservoir. Thus, our data provide a high-dimensional definition of the mechanisms of immune regulation that chronic viruses implement to exploit the unique microenvironment of the GIT and identify T reg cells as key modulators of viral persistence in the intestinal tract.
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http://dx.doi.org/10.1084/jem.20191473DOI Listing
December 2020

Chronic virus infection drives CD8 T cell-mediated thymic destruction and impaired negative selection.

Proc Natl Acad Sci U S A 2020 03 24;117(10):5420-5429. Epub 2020 Feb 24.

Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2M9, Canada;

Chronic infection provokes alterations in inflammatory and suppressive pathways that potentially affect the function and integrity of multiple tissues, impacting both ongoing immune control and restorative immune therapies. Here we demonstrate that chronic lymphocytic choriomeningitis virus infection rapidly triggers severe thymic depletion, mediated by CD8 T cell-intrinsic type I interferon (IFN) and signal transducer and activator of transcription 2 (Stat2) signaling. Occurring temporal to T cell exhaustion, thymic cellularity reconstituted despite ongoing viral replication, with a rapid secondary thymic depletion following immune restoration by anti-programmed death-ligand 1 (PDL1) blockade. Therapeutic hematopoietic stem cell transplant (HSCT) during chronic infection generated new antiviral CD8 T cells, despite sustained virus replication in the thymus, indicating an impairment in negative selection. Consequently, low amounts of high-affinity self-reactive T cells also escaped the thymus following HSCT during chronic infection. Thus, by altering the stringency and partially impairing negative selection, the host generates new virus-specific T cells to replenish the fight against the chronic infection, but also has the potentially dangerous effect of enabling the escape of self-reactive T cells.
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http://dx.doi.org/10.1073/pnas.1913776117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071912PMC
March 2020

Validation of CyTOF Against Flow Cytometry for Immunological Studies and Monitoring of Human Cancer Clinical Trials.

Front Oncol 2019 17;9:415. Epub 2019 May 17.

Tumor Immunology Program, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.

Flow cytometry is a widely applied approach for exploratory immune profiling and biomarker discovery in cancer and other diseases. However, flow cytometry is limited by the number of parameters that can be simultaneously analyzed, severely restricting its utility. Recently, the advent of mass cytometry (CyTOF) has enabled high dimensional and unbiased examination of the immune system, allowing simultaneous interrogation of a large number of parameters. This is important for deep interrogation of immune responses and particularly when sample sizes are limited (such as in tumors). Our goal was to compare the accuracy and reproducibility of CyTOF against flow cytometry as a reliable analytic tool for human PBMC and tumor tissues for cancer clinical trials. We developed a 40+ parameter CyTOF panel and demonstrate that compared to flow cytometry, CyTOF yields analogous quantification of cell lineages in conjunction with markers of cell differentiation, function, activation, and exhaustion for use with fresh and viably frozen PBMC or tumor tissues. Further, we provide a protocol that enables reliable quantification by CyTOF down to low numbers of input human cells, an approach that is particularly important when cell numbers are limiting. Thus, we validate CyTOF as an accurate approach to perform high dimensional analysis in human tumor tissue and to utilize low cell numbers for subsequent immunologic studies and cancer clinical trials.
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http://dx.doi.org/10.3389/fonc.2019.00415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534060PMC
May 2019

CD8 T Cell Priming in Established Chronic Viral Infection Preferentially Directs Differentiation of Memory-like Cells for Sustained Immunity.

Immunity 2018 10 9;49(4):678-694.e5. Epub 2018 Oct 9.

Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada; Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8 Canada. Electronic address:

CD8 T cell exhaustion impedes control of chronic viral infection; yet how new T cell responses are mounted during chronic infection is unclear. Unlike T cells primed at the onset of infection that rapidly differentiate into effectors and exhaust, we demonstrate that virus-specific CD8 T cells primed after establishment of chronic LCMV infection preferentially generate memory-like transcription factor TCF1 cells that were transcriptionally and proteomically distinct, less exhausted, and more responsive to immunotherapy. Mechanistically, adaptations of antigen-presenting cells and diminished T cell signaling intensity promoted differentiation of the memory-like subset at the expense of rapid effector cell differentiation, which was now highly dependent on IL-21-mediated CD4 T cell help for its functional generation. Chronic viral infection similarly redirected de novo differentiation of tumor-specific CD8 T cells, ultimately preventing cancer control. Thus, targeting these T cell stimulatory pathways could enable strategies to control chronic infection, tumors, and enhance immunotherapeutic efficacy.
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http://dx.doi.org/10.1016/j.immuni.2018.08.002DOI Listing
October 2018

A CD103 Conventional Dendritic Cell Surveillance System Prevents Development of Overt Heart Failure during Subclinical Viral Myocarditis.

Immunity 2017 11;47(5):974-989.e8

Toronto General Hospital Research Institute, University Health Network (UHN), Toronto ON, M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto ON, M5S 1A1, Canada; Department of Immunology, University of Toronto, Toronto ON, M5S 1A1, Canada; Peter Munk Cardiac Centre, Toronto ON, M5G 1L7, Canada; Ted Rogers Centre for Heart Research, Toronto ON, M5G 1L7, Canada. Electronic address:

Innate and adaptive immune cells modulate heart failure pathogenesis during viral myocarditis, yet their identities and functions remain poorly defined. We utilized a combination of genetic fate mapping, parabiotic, transcriptional, and functional analyses and demonstrated that the heart contained two major conventional dendritic cell (cDC) subsets, CD103 and CD11b, which differentially relied on local proliferation and precursor recruitment to maintain their tissue residency. Following viral infection of the myocardium, cDCs accumulated in the heart coincident with monocyte infiltration and loss of resident reparative embryonic-derived cardiac macrophages. cDC depletion abrogated antigen-specific CD8 T cell proliferative expansion, transforming subclinical cardiac injury to overt heart failure. These effects were mediated by CD103 cDCs, which are dependent on the transcription factor BATF3 for their development. Collectively, our findings identified resident cardiac cDC subsets, defined their origins, and revealed an essential role for CD103 cDCs in antigen-specific T cell responses during subclinical viral myocarditis.
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http://dx.doi.org/10.1016/j.immuni.2017.10.011DOI Listing
November 2017

Purging Exhausted Virus-Specific CD8 T Cell Phenotypes by Somatic Cell Reprogramming.

AIDS Res Hum Retroviruses 2017 Nov;33(S1):S59-S69

1 Division of Hematology and Oncology, David Geffen School of Medicine at UCLA , Los Angeles, California.

Cytotoxic T cells are critical in controlling virus infections. However, continuous antigen stimulation and negative regulatory factors cause CD8 T cells to enter a dysfunctional state (T cell exhaustion), resulting in viral persistence. We hypothesized that the exhausted T cell state could be molecularly rejuvenated using a somatic cell reprogramming technology, which is technically able to convert any types of cells to induced pluripotent stem cells (iPSCs), to regenerate functional T cells capable of purging chronic infection. We generated a new mouse line (B6/129) in which every somatic cell contains four doxycycline-inducible reprogramming genes (Oct4, Klf4, Sox2, and c-Myc: OKSM), and infected them with lymphocytic choriomeningitis virus (LCMV) clone 13 to establish chronic infection. Exhausted LCMV-specific T cells isolated by flow sorting were successfully reprogrammed ex vivo into iPSCs in the presence of doxycycline. Upon injection into blastocysts and subsequent transfer into foster females, the reprogrammed cells differentiated into functional naive T cells that maintained their original antigen specificity. These results provide proof of concept that somatic cell reprogramming of exhausted T cells into iPSCs can erase imprints of their previous exhausted state and in turn regenerate functional virus-specific T cells.
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http://dx.doi.org/10.1089/aid.2017.0161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684681PMC
November 2017

Overcoming CD4 Th1 Cell Fate Restrictions to Sustain Antiviral CD8 T Cells and Control Persistent Virus Infection.

Cell Rep 2016 09;16(12):3286-3296

Princess Margaret Cancer Center, Immune Therapy Program, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

Viral persistence specifically inhibits CD4 Th1 responses and promotes Tfh immunity, but the mechanisms that suppress Th1 cells and the disease consequences of their loss are unclear. Here, we demonstrate that the loss of CD4 Th1 cells specifically leads to progressive CD8 T cell decline and dysfunction during viral persistence. Therapeutically reconstituting CD4 Th1 cells restored CD4 T cell polyfunctionality, enhanced antiviral CD8 T cell numbers and function, and enabled viral control. Mechanistically, combined interaction of PD-L1 and IL-10 by suppressive dendritic cell subsets inhibited new CD4 Th1 cells in both acute and persistent virus infection, demonstrating an unrecognized suppressive function for PD-L1 in virus infection. Thus, the loss of CD4 Th1 cells is a key event leading to progressive CD8 T cell demise during viral persistence with important implications for restoring antiviral CD8 T cell immunity to control persistent viral infection.
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http://dx.doi.org/10.1016/j.celrep.2016.08.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669380PMC
September 2016

Type I interferon suppresses de novo virus-specific CD4 Th1 immunity during an established persistent viral infection.

Proc Natl Acad Sci U S A 2014 May 5;111(20):7409-14. Epub 2014 May 5.

Department of Microbiology, Immunology and Molecular Genetics andUCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and

CD4 T cells are central to orchestrate, sustain, and potentially regenerate antiviral immunity throughout persistent viral infections. Although the evolving immune environment during persistent infection reshapes established CD4 T-cell responses, the fate of naïve CD4 T cells primed in the midst of persistent infection is unclear. We demonstrate that, in marked contrast to the onset of infection, virus-specific CD4 T cells primed during an established persistent infection have diminished ability to develop Th1 responses, to efficiently accumulate in peripheral tissues, and almost exclusively differentiate into T follicular helper cells. Consistent with suppressed Th1 and heightened Tfh differentiation, virus-specific CD4 T cells primed during the established persistent infection provide help to B cells, but only limited help to CD8 T cells. The suppression of de novo Th1 generation and tissue distribution was mediated by chronic type I IFN (IFN-I) production and was effectively restored by blocking IFN-I signaling during CD4 T-cell priming. Thus, we establish a suppressive function of chronic IFN-I signaling and mechanism of immunoregulation during an established persistent virus infection.
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http://dx.doi.org/10.1073/pnas.1401662111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4034239PMC
May 2014

Selective inhibitor of endosomal trafficking pathways exploited by multiple toxins and viruses.

Proc Natl Acad Sci U S A 2013 Dec 4;110(50):E4904-12. Epub 2013 Nov 4.

Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095.

Pathogenic microorganisms and toxins have evolved a variety of mechanisms to gain access to the host-cell cytosol and thereby exert virulent effects upon the host. One common mechanism of cellular entry requires trafficking to an acidified endosome, which promotes translocation across the host membrane. To identify small-molecule inhibitors that block this process, a library of 30,000 small molecules was screened for inhibitors of anthrax lethal toxin. Here we report that 4-bromobenzaldehyde N-(2,6-dimethylphenyl)semicarbazone, the most active compound identified in the screen, inhibits intoxication by lethal toxin and blocks the entry of multiple other acid-dependent bacterial toxins and viruses into mammalian cells. This compound, which we named EGA, also delays lysosomal targeting and degradation of the EGF receptor, indicating that it targets host-membrane trafficking. In contrast, EGA does not block endosomal recycling of transferrin, retrograde trafficking of ricin, phagolysosomal trafficking, or phagosome permeabilization by Franciscella tularensis. Furthermore, EGA does not neutralize acidic organelles, demonstrating that its mechanism of action is distinct from pH-raising agents such as ammonium chloride and bafilomycin A1. EGA is a powerful tool for the study of membrane trafficking and represents a class of host-targeted compounds for therapeutic development to treat infectious disease.
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http://dx.doi.org/10.1073/pnas.1302334110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864319PMC
December 2013