Acquisition of lymphokine-producing phenotype by CD4+ T cells

Annu Rev Immunol. 1994;12:635-73. doi: 10.1146/annurev.iy.12.040194.003223.


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.

Publication types

  • Review

MeSH terms

  • Animals
  • Antigen-Presenting Cells / physiology
  • CD4-Positive T-Lymphocytes / physiology*
  • Humans
  • Interferon-gamma / biosynthesis
  • Interleukins / biosynthesis
  • Lymphocyte Activation
  • Lymphokines / biosynthesis*
  • Lymphokines / physiology
  • T-Lymphocytes, Helper-Inducer / physiology
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Interleukins
  • Lymphokines
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma