Weak TCR stimulation induces a calcium signal that triggers IL-4 synthesis, stronger TCR stimulation induces MAP kinases that control IFN-gamma production

Th1 and Th2 cells produce different cytokines and have distinct functions. Th1/Th2 cell differentiation is influenced, among other factors, by the nat ure of TCR-MHC interactions. However, how the TCR transduces a signal resul ting in IFN-gamma or IL-4 production is a matter of debate. For example, so me authors reported a loss of calcium signaling pathway in Th2 cells. We us ed a T cell hybridoma producing IL-4 upon weak TCR stimulation and both IL- 4 and IFN-gamma for strong TCR engagement as a model to study how TCR signa ling pathways are differentially activated in both conditions of stimulatio n and how this influences the production of cytokines. We show that: (1) th e calcium response is identical following weak and strong TCR stimulation; (2) mitogen-activated protein kinase (MAPK) activation is a gradual phenome non depending upon the strength of TCR activation; (3) a calcium response, even weak, triggers IL-4 expression; (4) IFN-gamma synthesis requires not o nly a calcium response but also MAPK activation. The MAPK pathway is dispen sable for IL-4 production, although it amplifies IL-4 synthesis upon strong TCR stimulation; (5) TCR-induced IL-4 production also depends on calcium s ignaling in Th2 cells, while IFN-gamma synthesis is dependent, in addition, on MAPK activation in Th1 cells.