Publications by authors named "Harikesh S Wong"

8 Publications

  • Page 1 of 1

A local regulatory T cell feedback circuit maintains immune homeostasis by pruning self-activated T cells.

Cell 2021 Jul 21;184(15):3981-3997.e22. Epub 2021 Jun 21.

Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA. Electronic address:

A fraction of mature T cells can be activated by peripheral self-antigens, potentially eliciting host autoimmunity. We investigated homeostatic control of self-activated T cells within unperturbed tissue environments by combining high-resolution multiplexed and volumetric imaging with computational modeling. In lymph nodes, self-activated T cells produced interleukin (IL)-2, which enhanced local regulatory T cell (Treg) proliferation and inhibitory functionality. The resulting micro-domains reciprocally constrained inputs required for damaging effector responses, including CD28 co-stimulation and IL-2 signaling, constituting a negative feedback circuit. Due to these local constraints, self-activated T cells underwent transient clonal expansion, followed by rapid death ("pruning"). Computational simulations and experimental manipulations revealed the feedback machinery's quantitative limits: modest reductions in Treg micro-domain density or functionality produced non-linear breakdowns in control, enabling self-activated T cells to subvert pruning. This fine-tuned, paracrine feedback process not only enforces immune homeostasis but also establishes a sharp boundary between autoimmune and host-protective T cell responses.
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http://dx.doi.org/10.1016/j.cell.2021.05.028DOI Listing
July 2021

Gut Helicobacter presentation by multiple dendritic cell subsets enables context-specific regulatory T cell generation.

Elife 2021 Feb 3;10. Epub 2021 Feb 3.

Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, United States.

Generation of tolerogenic peripheral regulatory T (pTreg) cells is commonly thought to involve CD103 gut dendritic cells (DCs), yet their role in commensal-reactive pTreg development is unclear. Using two Helicobacterspecific T cell receptor (TCR) transgenic mouse lines, we found that both CD103 and CD103 migratory, but not resident, DCs from the colon-draining mesenteric lymph node presented Helicobacter antigens to T cells ex vivo. Loss of most CD103 migratory DCs in vivo using murine genetic models did not affect the frequency of Helicobacter-specific pTreg cell generation or induce compensatory tolerogenic changes in the remaining CD103 DCs. By contrast, activation in a Th1-promoting niche in vivo blocked Helicobacter-specific pTreg generation. Thus, these data suggest a model where DC-mediated effector T cell differentiation is 'dominant', necessitating that all DC subsets presenting antigen are permissive for pTreg cell induction to maintain gut tolerance.
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http://dx.doi.org/10.7554/eLife.54792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877908PMC
February 2021

Commensal-driven immune zonation of the liver promotes host defence.

Nature 2021 01 25;589(7840):131-136. Epub 2020 Nov 25.

Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

The liver connects the intestinal portal vasculature with the general circulation, using a diverse array of immune cells to protect from pathogens that translocate from the gut. In liver lobules, blood flows from portal triads that are situated in periportal lobular regions to the central vein via a polarized sinusoidal network. Despite this asymmetry, resident immune cells in the liver are considered to be broadly dispersed across the lobule. This differs from lymphoid organs, in which immune cells adopt spatially biased positions to promote effective host defence. Here we used quantitative multiplex imaging, genetic perturbations, transcriptomics, infection-based assays and mathematical modelling to reassess the relationship between the localization of immune cells in the liver and host protection. We found that myeloid and lymphoid resident immune cells concentrate around periportal regions. This asymmetric localization was not developmentally controlled, but resulted from sustained MYD88-dependent signalling induced by commensal bacteria in liver sinusoidal endothelial cells, which in turn regulated the composition of the pericellular matrix involved in the formation of chemokine gradients. In vivo experiments and modelling showed that this immune spatial polarization was more efficient than a uniform distribution in protecting against systemic bacterial dissemination. Together, these data reveal that liver sinusoidal endothelial cells sense the microbiome, actively orchestrating the localization of immune cells, to optimize host defence.
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http://dx.doi.org/10.1038/s41586-020-2977-2DOI Listing
January 2021

Robust control of the adaptive immune system.

Semin Immunol 2018 04 29;36:17-27. Epub 2017 Dec 29.

Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA. Electronic address:

The adaptive immune system continually faces unpredictable circumstances yet reproducibly counteracts invading pathogens while limiting damage to self. However, the system is dynamic in nature: many of its internal components are not fixed, but rather, fluctuate over time. This concept is exemplified by αβ T lymphocytes, which vary significantly from cell-to-cell in their spatiotemporal dynamics, antigen-binding receptors, and subcellular protein concentrations. How are reproducible immune functions achieved in the face of such variability? This design principle is known as robustness and requires the system to employ layered control schemes that both buffer and exploit different facets of cellular variation. In this article, we discuss these schemes and their applications to individual αβ T cell responses as well as integrated population level behaviours.
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http://dx.doi.org/10.1016/j.smim.2017.12.009DOI Listing
April 2018

Chemokine Signaling Enhances CD36 Responsiveness toward Oxidized Low-Density Lipoproteins and Accelerates Foam Cell Formation.

Cell Rep 2016 Mar 17;14(12):2859-71. Epub 2016 Mar 17.

Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 2Z9, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada. Electronic address:

Excessive uptake of oxidized low-density lipoproteins (oxLDL) by macrophages is a fundamental characteristic of atherosclerosis. However, signals regulating the engagement of these ligands remain elusive. Using single-molecule imaging, we discovered a mechanism whereby chemokine signaling enhanced binding of oxLDL to the scavenger receptor, CD36. By activating the Rap1-GTPase, chemokines promoted integrin-mediated adhesion of macrophages to the substratum. As a result, cells exhibited pronounced remodeling of the cortical actin cytoskeleton that increased CD36 clustering. Remarkably, CD36 clusters formed predominantly within actin-poor regions of the cortex, and these regions were primed to engage oxLDL. In accordance with enhanced ligand engagement, prolonged exposure of macrophages to chemokines amplified the accumulation of esterified cholesterol, thereby accentuating the foam cell phenotype. These findings imply that the activation of integrins by chemokine signaling exerts feedforward control over receptor clustering and effectively alters the threshold for cells to engage ligands.
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http://dx.doi.org/10.1016/j.celrep.2016.02.071DOI Listing
March 2016

Toll-like receptor ligands sensitize B-cell receptor signalling by reducing actin-dependent spatial confinement of the receptor.

Nat Commun 2015 Feb 3;6:6168. Epub 2015 Feb 3.

1] Department of Microbiology &Immunology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3 [2] Life Sciences Institute I3 and Cell Research Groups, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3.

Integrating signals from multiple receptors allows cells to interpret the physiological context in which a signal is received. Here we describe a mechanism for receptor crosstalk in which receptor-induced increases in actin dynamics lower the threshold for signalling by another receptor. We show that the Toll-like receptor ligands lipopolysaccharide and CpG DNA, which are conserved microbial molecules, enhance signalling by the B-cell antigen receptor (BCR) by activating the actin-severing protein cofilin. Single-particle tracking reveals that increased severing of actin filaments reduces the spatial confinement of the BCR within the plasma membrane and increases BCR mobility. This allows more frequent collisions between BCRs and greater signalling in response to low densities of membrane-bound antigen. These findings implicate actin dynamics as a means of tuning receptor signalling and as a mechanism by which B cells distinguish inert antigens from those that are accompanied by indicators of microbial infection.
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http://dx.doi.org/10.1038/ncomms7168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4327415PMC
February 2015

Cytoskeletal confinement of CX3CL1 limits its susceptibility to proteolytic cleavage by ADAM10.

Mol Biol Cell 2014 Dec 24;25(24):3884-99. Epub 2014 Sep 24.

Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada Department of Paediatrics, University of Toronto, Toronto, ON M5S 2J7, Canada

CX3CL1 is a unique chemokine that acts both as a transmembrane endothelial adhesion molecule and, upon proteolytic cleavage, a soluble chemoattractant for circulating leukocytes. The constitutive release of soluble CX3CL1 requires the interaction of its transmembrane species with the integral membrane metalloprotease ADAM10, yet the mechanisms governing this process remain elusive. Using single-particle tracking and subdiffraction imaging, we studied how ADAM10 interacts with CX3CL1. We observed that the majority of cell surface CX3CL1 diffused within restricted confinement regions structured by the cortical actin cytoskeleton. These confinement regions sequestered CX3CL1 from ADAM10, precluding their association. Disruption of the actin cytoskeleton reduced CX3CL1 confinement and increased CX3CL1-ADAM10 interactions, promoting the release of soluble chemokine. Our results demonstrate a novel role for the cytoskeleton in limiting membrane protein proteolysis, thereby regulating both cell surface levels and the release of soluble ligand.
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http://dx.doi.org/10.1091/mbc.E13-11-0633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4244198PMC
December 2014
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