The Hunt for the Source of Primary Interleukin-4: How We Discovered That Natural Killer T Cells and Basophils Determine T Helper Type 2 Cell Differentiation In Vivo.

Tomohiro Yoshimoto

doi:10.3389/fimmu.2018.00716

Abstract

Interleukin (IL)-4 plays a central role in determining the phenotype of naïve CD4+ T cells by promoting their differentiation into IL-4-producing T helper type 2 (Th2) cells, which are crucial for the induction of allergic inflammation. However, to date, the potential sources of “primary IL-4” in vivo, as distinguished from IL-4 produced by Th2 cells, remain unclear. Here, I describe the research I carried out in collaboration with Dr. William E. Paul to identify “primary IL-4”-producing cells and Th2 cell differentiation in vivo.

Highlights

In 1986, Coffman and Mosmann proposed the T helper (Th) dichotomy, in which they showed the presence of two different cell subsets, consisting of Th1 and Th2 CD4+ T cell lineages each expressing a definite cytokine profile [1]
It is well established that the differentiation of naïve CD4+ T cells into Th1 or Th2 cells requires three signals: [1] T cell receptor (TCR) triggering through antigen recognition by MHC class II molecules; [2] augmentation of TCR signaling via co-stimulatory molecules, such as CD80 and/ or CD86 and CD28; and [3] an appropriate cytokine, e.g., IL-12 for Th1 cell [4, 5] and IL-4 for Th2 cell differentiation [6, 7]
We demonstrated that in addition to IL-4 production, naïve CD4+ T cells stimulated with IL-2 and IL-18 for 4 days upregulated CD40 ligand (CD40L) and induced B cells to secrete IgE in vitro [23]

Summary

INTRODUCTION

In 1986, Coffman and Mosmann proposed the T helper (Th) dichotomy, in which they showed the presence of two different cell subsets, consisting of Th1 and Th2 CD4+ T cell lineages each expressing a definite cytokine profile [1]. Sokol et al showed that Th2 cell differentiation was increased in the presence of papain, which stimulated basophils to increase the expression of MHC class II and the production of IL-4 [37], indicating that protease allergen activated basophils to augment their presentation of allergen to CD4+ T cells Do basophils increase their potential to act as APCs when stimulated with antigen and antigen-specific IgE? These Th2 responses were significantly diminished in basophildepleted mice [11] These results clearly demonstrated that basophils contribute to the development and the augmentation of antigen-specific Th2 cells in vivo by taking up the complex of antigen and antigen-specific IgE, presenting antigen peptide along with MHC class II and producing large amounts of IL-4 (Figure 3)

CONTROVERSIES IN THIS FIELD OF BASOPHILS

Findings

CONCLUDING REMARKS