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

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.

Parasitic Nematodes Exert Antimicrobial Activity and Benefit From Microbiota-Driven Support for Host Immune Regulation

“…Calculating the ratios of Th2 cells to Treg based on their frequencies in CD4 + T cells, we found significantly elevated Th2 effector to Treg ratios in the small intestine of infected GF compared to SPF mice (Figure 5C ). We have previously shown that intestinal nematode infections lead to the differentiation of GATA-3 + Th2 and GATA-3 + T-bet + Th2/1 hybrid cells ( 51 , 52 ). Th2/1 cells developed in infected SPF as well as GF mic, hence microbial signals were dispensable for their induction (Figures 5D,E ).…”

A Mechanistic Computational Model Reveals That Plasticity of CD4+ T Cell Differentiation Is a Function of Cytokine Composition and Dosage

“…The Th2 cells have been reported to further develop into Th9 cells ( Veldhoen et al, 2008 ). More complexity in T cell differentiation was observed in the form of co-expression of mutually exclusive lineage-specifying transcription factors (TFs) ( Peine et al, 2013 ; Bock et al, 2017 ). This co-expression can lead to the development of stable or intermediate subtypes that share characteristics of more than one type of T cell ( Tartar et al, 2010 ).…”

Manipulation of the balance between Th2 and Th2/1 hybrid cells affects parasite nematode fitness in mice

“…Effective lineage commitment is enforced by positive feedback mechanisms and reciprocal inhibition of the opposing developmental program, suggesting that Th2 and Th1 differentiation are mutually exclusive . However, many CD4 + T cells activated in helminth infections acquire a Th2/1 hybrid phenotype in stably coexpressing GATA‐3/T‐bet and Th2 cytokines with IFN‐γ . Th2/1 cells display lower immunopathological potential than Th1 or Th2 cells and are detectable in nematode‐infected humans .…”

“…However, many CD4 + T cells activated in helminth infections acquire a Th2/1 hybrid phenotype in stably coexpressing GATA‐3/T‐bet and Th2 cytokines with IFN‐γ . Th2/1 cells display lower immunopathological potential than Th1 or Th2 cells and are detectable in nematode‐infected humans .…”