Differentiation of naive human CD4 T cells into TH2/TH1 effectors

ABSTRACTThe mechanisms regulating the differentiation of naive CD4 T cells into Th1/Th2 subsets have been intensively investigated in the mouse. This report summarizes the current knowledge regarding naive human CD4 T cell maturation in vitro. The Thl/Th2 dichotomy is less absolute in human than in mouse T cells; indeed, unlike their murine counterparts, human Th2 cells retain the capacity for responding to and of inducing the production of interleukin (IL)-l2. When adequately stimulated, naive CD4 T cells release not only IL-2, but also high levels of type 1 cytokines (interferon (IFN)-γ, lymphotoxin and tumor necrosis factor (TNF)-α) as well as low levels of type 2 cytokines (IL-4, IL-13 and IL-10). lnterleukin-4 may be produced by every single naive T cell at very low levels that are sufficient to promote the acquisition of a Th2 phenotype upon repetitive stimulation in the absence of exogenous cytokine. Interleukin-l2 primes naive T cells for increased production of IFN-γ, decreased production of IL-4 and IL-5 and increased responsiveness to IL-12. The effects of IL-12 on IFN-γ and IL-5 as well as on IL-12 responsiveness are prolonged, whereas those on IL-4 are transient. However, repetitive stimulation in the presence of IL-12 leads to Thl effectors. Thus, IL-12 is required not only for the induction but also for the development and maintenance of a Thl response. Upon interaction with dendritic cells (DC), naive T cells produce several cytokines (IL-4, IFN-γ) and express CD40L, which triggers IL-1 2 production by DC. The balance between these endogenously produced cytokines determines the lymphokine-producing phenotype of primed cells, this balance depending upon the genetic background, the nature and the strength of the T-cell-receptor-mediated signal and the activation state of DC