Th2/1 Hybrid Cells Occurring in Murine and Human Strongyloidiasis Share Effector Functions of Th1 Cells

Front Cell Infect Microbiol. 2017 Jun 20;7:261. doi: 10.3389/fcimb.2017.00261. eCollection 2017.

Abstract

Infections by the soil-transmitted threadworm Strongyloides stercoralis affect 30-100 million people worldwide, predominantly in tropic and sub-tropic regions. Here we assessed the T helper cell phenotypes in threadworm-infected patients and experimental murine infections with focus on CD4+ T cells co-expressing markers of Th2 and Th1 differentiation. We show that mice infected with the close relative S. ratti generate strong Th2 responses characterized by the expansion of CD4+ GATA-3+ cells expressing IL-4/-5/-13 in blood, spleen, gut-draining lymph nodes, lung and gut tissue. In addition to conventional Th2 cells, significantly increased frequencies of GATA-3+T-bet+ Th2/1-hybrid cells were detected in all organs and co-expressed Th2- and Th1-cytokines at intermediate levels. Assessing the phenotype of blood-derived CD4+ T cells from South Indian patients infected with S. stercoralis and local uninfected control donors we found that GATA-3 expressing Th2 cells were significantly increased in the patient cohort, coinciding with elevated eosinophil and IgE/IgG4 levels. A fraction of IL-4+CD4+ T cells simultaneously expressed IFN-γ hence displaying a Th2/1 hybrid phenotype. In accordance with murine Th2/1 cells, human Th2/1 cells expressed intermediate levels of Th2 cytokines. Contrasting their murine counterparts, human Th2/1 hybrids were marked by high levels of IFN-γ and rather low GATA-3 expression. Assessing the effector function of murine Th2/1 cells in vitro we found that Th2/1 cells were qualified for driving the classical activation of macrophages. Furthermore, Th2/1 cells shared innate, cytokine-driven effector functions with Th1 cells. Hence, the key findings of our study are that T helper cells with combined characteristics of Th2 and Th1 cells are integral to immune responses of helminth-infected mice, but also occur in helminth-infected humans and we suggest that Th2/1 cells are poised for the instruction of balanced immune responses during nematode infections.

Keywords: GATA-3; T-bet; Th2; co-expression; cytokines; hybrid; nematode; strongyloides.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • Cytokines / blood
  • Female
  • GATA3 Transcription Factor / metabolism
  • Humans
  • Hybrid Cells / immunology*
  • Hybrid Cells / metabolism
  • Immunoglobulin E / blood
  • Immunoglobulin G / blood
  • India
  • Interferon-gamma
  • Interleukin-13 / blood
  • Interleukin-4 / blood
  • Interleukin-5 / blood
  • Intestine, Small / pathology
  • Lung / pathology
  • Lymph Nodes / pathology
  • Male
  • Mice
  • Middle Aged
  • Spleen / pathology
  • Strongyloides ratti / genetics
  • Strongyloides ratti / pathogenicity*
  • Strongyloidiasis / immunology*
  • Strongyloidiasis / pathology
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism
  • Young Adult

Substances

  • Cytokines
  • GATA3 Transcription Factor
  • GATA3 protein, human
  • Immunoglobulin G
  • Interleukin-13
  • Interleukin-5
  • Interleukin-4
  • Immunoglobulin E
  • Interferon-gamma