1. Immunology and Inflammation
  2. Microbiology and Infectious Disease
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An Integrin/MFG-E8 shuttle loads HIV-1 viral like particles onto follicular dendritic cells in mouse lymph node

  1. Chung Park
  2. John H Kehrl  Is a corresponding author
  1. National Institutes of Allergy and Infectious Diseases, United States
Research Article
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Cite this article as: eLife 2019;8:e47776 doi: 10.7554/eLife.47776


During human immunodeficiency virus-1 (HIV-1) infection lymphoid organ follicular dendritic cells (FDCs) serve as a reservoir for infectious virus and an obstacle to curative therapies. Here, we identify a subset of lymphoid organ sinus lining macrophage (SMs) that provide a cell-cell contact portal, which facilitates the uptake of HIV-1 viral like particles (VLPs) by FDCs and B cells in mouse lymph node. Central for portal function is the bridging glycoprotein MFG-E8. Using a phosphatidylserine binding domain and an RGD motif, MFG-E8 helps target HIV-1 VLPs to av integrin bearing SMs. Lack of MFG-E8 or integrin blockade severely limits HIV-1 VLP spread onto FDC networks. Direct SM-FDC virion transfer also depends upon short-lived FDC network abutment, likely triggered by SCSM antigen uptake. This provides a mechanism for rapid FDC loading broadening the opportunity for rare, antigen reactive follicular B cells to acquire antigen, and a means for HIV virions to accumulate on the FDC network.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Chung Park

    B-cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institutes of Allergy and Infectious Diseases, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. John H Kehrl

    B-cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institutes of Allergy and Infectious Diseases, Bethesda, United States
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6526-159X


No external funding was received for this work.


Animal experimentation: The NIAID Animal Care and Use Committee (ACUC) at the National Institutes of Health approved all the animal experiments and protocols used in the study, under protocol LIR-15E.

Human subjects: Human peripheral blood mononuclear cells (PBMCs) were collected from healthy donors through a NIH Department of Transfusion Medicine protocol that was approved by the Institutional Review Board of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health.

Reviewing Editor

  1. Facundo D Batista, Ragon Institute of MGH, MIT and Harvard, United States

Publication history

  1. Received: April 17, 2019
  2. Accepted: November 8, 2019
  3. Accepted Manuscript published: December 3, 2019 (version 1)
  4. Accepted Manuscript updated: December 6, 2019 (version 2)
  5. Version of Record published: December 9, 2019 (version 3)


This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.


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Further reading

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    Despite antigen affinity of B cells varying from cell to cell, functional analyses of antigen-reactive B cells on individual B cells are missing due to technical difficulties. Especially in the field of autoimmune diseases, promising pathogenic B cells have not been adequately studied to date because of its rarity. In this study, functions of autoantigen-reactive B cells in autoimmune disease were analyzed at the single-cell level. Since topoisomerase I is a distinct autoantigen, we targeted systemic sclerosis as autoimmune disease. Decreased and increased affinities for topoisomerase I of topoisomerase I-reactive B cells led to anti-inflammatory and pro-inflammatory cytokine production associated with the inhibition and development of fibrosis, which is the major symptom of systemic sclerosis. Furthermore, inhibition of pro-inflammatory cytokine production and increased affinity of topoisomerase I-reactive B cells suppressed fibrosis. These results indicate that autoantigen-reactive B cells contribute to the disease manifestations in autoimmune disease through their antigen affinity.

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    After antigenic activation, quiescent naive CD4+ T cells alter their metabolism to proliferate. This metabolic shift increases production of nucleotides, amino acids, fatty acids, and sterols. Here, we show that histone deacetylase 3 (HDAC3) is critical for activation of murine peripheral CD4+ T cells. HDAC3-deficient CD4+ T cells failed to proliferate and blast after in vitro TCR/CD28 stimulation. Upon T-cell activation, genes involved in cholesterol biosynthesis are upregulated while genes that promote cholesterol efflux are repressed. HDAC3-deficient CD4+ T cells had reduced levels of cellular cholesterol both before and after activation. HDAC3-deficient cells upregulate cholesterol synthesis appropriately after activation, but fail to repress cholesterol efflux; notably, they overexpress cholesterol efflux transporters ABCA1 and ABCG1. Repression of these genes is the primary function for HDAC3 in peripheral CD4+ T cells, as addition of exogenous cholesterol restored proliferative capacity. Collectively, these findings demonstrate HDAC3 is essential during CD4+ T-cell activation to repress cholesterol efflux.