Acquisition of Lymphokine-Producing Phenotype by CD4+ T Cells

Abstract

Naive CD4+ T cells when stimulated produce IL-2 as their major lymphokine. Upon priming, these cells develop into cells that produce either IFN gamma, TNF beta, and IL-2 or IL-4 and its congeners. The former cells are designated TH1-like, and the latter TH2-like. Here we review the regulation of the differentiation of naive CD4 cells into IFN gamma- or IL-4-producers. The dominant factors that determine such differentiation are lymphokines and other cytokines. IL-2 itself appears to be required for naive cells to develop into TH1- or TH2-like cells but is not deterministic of their differentiation fate. If IL-4 is also present during the priming period, the resultant CD4+ T cells produce IL-4 upon restimulation; the development of IFN gamma-producing cells is strikingly inhibited by IL-4. In the absence of IL-4, priming for IFN gamma-production occurs, but this is markedly enhanced by IL-12. The role of IFN gamma in enhancing priming for IFN gamma-production is not fully resolved. In some in vitro systems, it appears to act together with IL-12 to enhance such production. Anti-IFN gamma diminishes priming for IFN gamma production in vivo. Lymphokines also exert a "cross-regulatory" or inhibitory effect. As noted above, IL-4 strikingly diminishes priming for IFN gamma production, although this inhibitory effect is blunted in the presence of IL-12. IFN gamma similarly diminishes priming for IL-4 production; this effect is principally observed when low concentrations of IL-4 are used in the priming culture. Although other factors may play a role in the determination of lymphokine-producing phenotype, such as antigen dose, type of antigen-presenting cell, and expression of accessory molecules and hormones, these effects appear to be secondary to the dominant role of the lymphokines and cytokines.

Txk, a Nonreceptor Tyrosine Kinase of the Tec Family, Is Expressed in T Helper Type 1 Cells and Regulates Interferon γ Production in Human T Lymphocytes

“…It has been suggested that cytokines and their receptors, transcription factors, MHC determinants, Ag peptides, and costimulatory signals are important for Th1 and Th2 cell differentiation 1 2 3 4 5 6 7 8 9. However, to date, the precise mechanism responsible for the differentiation and development of polarized Th1 responses has not been fully clarified in humans.…”

Interleukin-4 enhances prostate-specific antigen expression by activation of the androgen receptor and Akt pathway

“…Interleukin-4 (IL-4) is a pleiotropic type I cytokine produced by T cells, mast cells, and basophils (Seder and Paul, 1994). IL-4 has biological effects on many immune cells, including B and T lymphocytes, mast cells, and macrophages, and plays a central role in regulating inflammatory and cell-mediated immune responses (Nelms et al, 1999).…”

TID1, a mammalian homologue of the drosophila tumor suppressor lethal(2) tumorous imaginal discs, regulates activation-induced cell death in Th2 cells

“…Th1 cells, which characteristically produce IFN-g, are derived by culturing CD4 T cells with antigen in the presence of IL-12, while Th2 cells that characteristically produce IL-4, IL-5 and IL-13 are derived by culturing CD4 T cells with antigen in the presence of IL-4 (Swain et al, 1991;O'Garra and Murphy, 1994;Seder and Paul, 1994). Upon activation, Th1 cell lines undergo AICD within 12-48 h, while Th2 cell lines are significantly more resistant (Varadhachary et al, 1997;Zhang et al, 1997;Carter et al, 1998).…”