Lymphocytes are a late evolutionary addition to the immune system of vertebrates, enabling effective host defense against a wide variety of pathogenic microbes. The effector cells of the immune system [HN1], T and B lymphocytes [HN2], undergo two distinct modes of differentiation; one endows them with specificity for a particular antigen, the other with specific effector functions (T H 1 versus T H 2 cytokine patterns for CD4+ T cells; specific antibody classes for B cells). Recombination of the V, D, and J segments of antigen receptor genes [HN3] results in the generation of populations of T and B lymphocytes that express a broad repertoire of antigen receptors. In this way, the immune system is able to respond to a wide array of pathogens. Binding of antigen to the corresponding receptor stimulates the lymphocyte bearing that receptor to differentiate. In the case of T cells, functional differentiation is accompanied by distinct expression patterns for genes encoding cytokines [HN4] and surface receptors. When stimulated by antigen, precursor T cells bearing the CD4 [HN5] marker [T helper (T H) cells] differentiate into either T H 1 cells or T H 2 cells [HN6]. T H 1 cells produce interferon-γ (IFN-γ) and tumor necrosis factor-β (TNF-β)[HN7] and protect against intracellular pathogens; T H 2 cells, which produce interleukin (IL)-4, IL-5, and IL-13 [HN8], help to control extracellular pathogens, and mediate allergy [HN9](1).

The best characterized influence on the differentiation of T H cells is the cytokine environment [HN10](1). T H cells first activated by antigen in the presence of IL-12 [HN11] develop predominantly into T H 1 cells, whereas those activated in the presence of IL-4 develop predominantly into T H 2 cells. There is a debate about whether the cytokines that induce T H 1 or T H 2 differentiation “instruct” the developmental fate of naïve T H cells or “select” for cells that through a random (stochastic) process of gene activation already produce a combination of cytokines indicative of a T H 1 or T H 2 cell (see the figure).