Circulating CXCR5+CXCR3+PD-1lo Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth

JCI Insight. 2017 Jan 26;2(2):e89574. doi: 10.1172/jci.insight.89574.

Abstract

HIV-1-specific broadly neutralizing antibodies (bnAbs) typically develop in individuals with continuous high-level viral replication and increased immune activation, conditions that cannot be reproduced during prophylactic immunization. Understanding mechanisms supporting bnAb development in the absence of high-level viremia may be important for designing bnAb-inducing immunogens. Here, we show that the breadth of neutralizing antibody responses in HIV-1 controllers was associated with a relative enrichment of circulating CXCR5+CXCR3+PD-1lo CD4+ T cells. These CXCR3+PD-1lo Tfh-like cells were preferentially induced in vitro by functionally superior dendritic cells from controller neutralizers, and able to secrete IL-21 and support B cells. In addition, these CXCR3+PD-1lo Tfh-like cells contained higher proportions of stem cell-like memory T cells, and upon antigenic stimulation differentiated into PD-1hi Tfh-like cells in a Notch-dependent manner. Together, these data suggest that CXCR5+CXCR3+PD-1lo cells represent a dendritic cell-primed precursor cell population for PD-1hi Tfh-like cells that may contribute to the generation of bnAbs in the absence of high-level viremia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIDS Vaccines
  • Anti-HIV Agents / therapeutic use
  • Antibodies, Neutralizing / immunology*
  • B-Lymphocytes
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Dendritic Cells
  • Disease Resistance / immunology
  • HIV Antibodies / immunology*
  • HIV Infections / drug therapy
  • HIV Infections / immunology*
  • HIV-1 / immunology*
  • Humans
  • Immunologic Memory / immunology
  • In Vitro Techniques
  • Interleukins / immunology
  • Interleukins / metabolism
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism
  • Receptors, CXCR3 / immunology
  • Receptors, CXCR3 / metabolism
  • Receptors, CXCR5 / immunology
  • Receptors, CXCR5 / metabolism
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism
  • Viremia / immunology

Substances

  • AIDS Vaccines
  • Anti-HIV Agents
  • Antibodies, Neutralizing
  • CXCR3 protein, human
  • CXCR5 protein, human
  • HIV Antibodies
  • Interleukins
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, CXCR3
  • Receptors, CXCR5
  • interleukin-21