T cell antigen receptor-mediated activation of the Ras/mitogen-activated protein kinase pathway controls interleukin 4 receptor function and type-2 helper T cell differentiation

T cell antigen receptor-mediated activation of the Ras/mitogen-activated protein kinase pathway controls interleukin 4 receptor function and type-2 helper T cell differentiation

^*Department of Developmental Immunology, Chiba University School of Medicine, and ^†Department of Molecular Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan; ^‡Research Institute for Biological Sciences, Science University of Tokyo, 2669 Yamazaki, Chiba 279-0022, Japan; and ^§Howard Hughes Medical Institute, and Departments of Immunology, Biochemistry, and Medicine, University of Washington, Seattle, WA 98195

Edited by Tony Hunter, The Salk Institute for Biological Studies, San Diego, CA, and approved December 2, 1998 (received for review August 21, 1998)

Abstract

The central role of type-2 helper T (Th2) cells in the development of allergic responses and immune responses against helminthic parasites is well documented. The differentiation of Th2 cells from naive T cells requires both the recognition of antigen by T cell antigen receptors (TCR) and the activation of downstream signal-transduction molecules of the interleukin 4 receptor (IL-4R) pathway, including Jak1, Jak3, and STAT6. Little is known, however, about how these two distinct pathways cooperate with each other to induce Th2 cells. Here, we use a T cell-specific H-Ras-dominant-negative transgenic mouse to show that TCR-mediated activation of the Ras/mitogen-activated protein kinase pathway alters IL-4R function and is required for Th2 cell differentiation. The enhancement of IL-4R signaling seems to be a consequence of both direct “crosstalk” with the TCR signaling pathway and increased protein expression of downstream signaling molecules of the IL-4R pathway. Therefore, successful Th2 differentiation depends on the effectiveness of the TCR-mediated activation of the Ras/mitogen-activated protein kinase pathway in modifying the IL-4R-mediated signaling pathway.

Footnotes

↵ ¶ To whom reprint requests should be addressed. e-mail: nakayama{at}med.m.chiba-u.ac.jp.
This paper was submitted directly (Track II) to the Proceedings Office.
ABBREVIATIONS:

B6,

C57BL/6;

dnRas,

H-Ras dominant negative;

DO10,

anti-OVA-specific TCRαβ;

IFN,

interferon;

IL,

interleukin;

IL-4R,

interleukin 4 receptor;

Lck,

lymphoid cell protein tyrosine kinase p56LCK;

LM,

littermate;

MAPK,

mitogen-activated protein kinase;

MAPKK,

MAPK kinase;

OVA,

ovalbumin;

PMA,

phorbol 12-myristate 13-acetate;

TCR,

T cell antigen receptor;

Tg,

transgenic;

Th1,

type-1 helper T;

Th2,

type-2 helper T;

TNP,

2,4,6-trinitrophenyl