CD4+ T Cell-derived Novel Peptide Thp5 Induces Interleukin-4 Production in CD4+ T Cells to Direct T Helper 2 Cell Differentiation

Mohd Moin Khan,Samit Chatterjee,Ved Prakash Dwivedi,Nishant Kumar Pandey,Yogesh Singh,Sultan Tousif,Neel Sarovar Bhavesh,Luc Van Kaer,Jyoti Das,Gobardhan Das

doi:10.1074/jbc.m111.319947

Abstract

The differentiation of naïve CD4(+) T cells into T helper 2 (Th2) cells requires production of the cytokine IL-4 in the local microenvironment. It is evident that naïve/quiescently activated CD4(+) T cells produce the IL-4 that drives Th2 cell differentiation. Because early production of IL-4 in naïve T cells leads to preferential Th2 cell differentiation, this process needs to be tightly regulated so as to avoid catastrophic and misdirected Th2 cell differentiation. Here, we show that Thp5, a novel peptide with structural similarity to vasoactive intestinal peptide, regulates production of early IL-4 in newly activated CD4(+) T cells. Induction of IL-4 in CD4(+) T cells by Thp5 is independent of the transcription factor STAT6 but dependent on ERK1/2 signaling. Furthermore, cytokines (IL-12 and TGF-β) that promote the differentiation of Th1 or Th17 cells inhibit Thp5 induction, thus suppressing Th2 cell differentiation. We further showed that Thp5 enhances Th2 responses and exacerbates allergic airway inflammation in mice. Taken together, our findings reveal that early activated CD4(+) T cells produce Thp5, which plays a critical role as a molecular switch in the differentiation of Th cells, biasing the response toward the Th2 cell phenotype.

Highlights

CD4ϩ T cells produce IL-4 that drives T helper 2 (Th2) cell differentiation
Our findings reveal that early activated CD4؉ T cells produce T helper cell-induced peptide 5 (Thp5), which plays a critical role as a molecular switch in the differentiation of Th cells, biasing the response toward the Th2 cell phenotype
We repeatedly found expression of a small protein/peptide designated Thp5, that is dramatically up-regulated in CD4ϩ T cells early after activation (Fig. 1B)

Summary

Background

CD4ϩ T cells produce IL-4 that drives Th2 cell differentiation. Early production of IL-4 in naïve T cells leads to Th2 cell differentiation. We show that Thp, a novel peptide with structural similarity to vasoactive intestinal peptide, regulates production of early IL-4 in newly activated CD4؉ T cells. Our findings reveal that early activated CD4؉ T cells produce Thp, which plays a critical role as a molecular switch in the differentiation of Th cells, biasing the response toward the Th2 cell phenotype. It has been reported that freshly activated naïve CD4ϩ T cells produce IL-4 that can drive Th2 differentiation in some settings (4 – 6). As this early IL-4 is the key determinant for the differentiation of Th2 cells, its production must be tightly regulated so as to avoid unwanted biased Th2 responses. We show that T helper cell-induced peptide 5 (Thp5), a novel peptide with structural similarity to vasoactive intestinal peptide, regulates production of early IL-4 in newly activated

The abbreviations used are

EXPERIMENTAL PROCEDURES

RESULTS AND DISCUSSION