Gut-homing Δ42PD1+Vδ2 T cells promote innate mucosal damage via TLR4 during acute HIV type 1 infection

Nat Microbiol. 2017 Oct;2(10):1389-1402. doi: 10.1038/s41564-017-0006-5. Epub 2017 Aug 14.

Abstract

The innate immune cells underlying mucosal inflammatory responses and damage during acute HIV-1 infection remain incompletely understood. Here, we report a Vδ2 subset of gut-homing γδ T cells with significantly upregulated Δ42PD1 (a PD1 isoform) in acute (~20%) HIV-1 patients compared to chronic HIV-1 patients (~11%) and healthy controls (~2%). The frequency of Δ42PD1+Vδ2 cells correlates positively with plasma levels of pro-inflammatory cytokines and fatty-acid-binding protein before detectable lipopolysaccharide in acute patients. The expression of Δ42PD1 can be induced by in vitro HIV-1 infection and is accompanied by high co-expression of gut-homing receptors CCR9/CD103. To investigate the role of Δ42PD1+Vδ2 cells in vivo, they were adoptively transferred into autologous humanized mice, resulting in small intestinal inflammatory damage, probably due to the interaction of Δ42PD1 with its cognate receptor Toll-like receptor 4 (TLR4). In addition, blockade of Δ42PD1 or TLR4 successfully reduced the cytokine effect induced by Δ42PD1+Vδ2 cells in vitro, as well as the mucosal pathological effect in humanized mice. Our findings have therefore uncovered a Δ42PD1-TLR4 pathway exhibited by virus-induced gut-homing Vδ2 cells that may contribute to innate immune activation and intestinal pathogenesis during acute HIV-1 infection. Δ42PD1+Vδ2 cells may serve as a target for the investigation of diseases with mucosal inflammation.

MeSH terms

  • Animals
  • Beijing
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / pathology
  • Cell Line
  • Cell Movement / immunology
  • Cytokines / metabolism
  • Disease Models, Animal
  • HIV Infections / immunology*
  • HIV Infections / pathology
  • HIV-1 / immunology*
  • HIV-1 / pathogenicity
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immunity, Innate / immunology
  • Immunity, Mucosal*
  • Intestine, Small / immunology
  • Intestine, Small / pathology
  • Intestines / immunology*
  • Lipopolysaccharides
  • Mice
  • Mucous Membrane / immunology*
  • Receptors, CCR / metabolism
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocyte Subsets / pathology
  • T-Lymphocyte Subsets / virology
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 4 / metabolism*

Substances

  • CC chemokine receptor 9
  • Cytokines
  • Lipopolysaccharides
  • Receptors, CCR
  • TLR4 protein, human
  • Toll-Like Receptor 4