Default development of cloned human naive CD4 T cells into interleukin‐4‐ and interleukin‐5‐producing effector cells

It was recently demonstrated that naive human and mouse CD4 T cells release low but sufficient levels of interleukin (IL)‐4 at priming to support their development into IL‐4 producers. To determine whether this IL‐4 is produced by a minor subset of cells, freshly isolated human naive CD4 T cells were directly cloned by limiting dilution in the absence of exogenous IL‐4. More than 95% of neonatal and 60% of adult naive T cells seeded in single‐cell cultures could be expanded upon stimulation with anti‐CD3 mAb immobilized on CD32‐B7.1 L cell transfectants in the presence of IL‐2. All 171 clones derived from four neonates and two adults produced IL‐4 and IL‐5 at generally high levels. Like the allergen‐specific human Th2 clones described in the literature, these T cell clones produced little or no interferon γ upon stimulation via their T cell receptor/CD3 complex, whereas they released high levels of this cytokine when activated with phorbol 12‐myristate 13‐acetate + ionomycin. Cells cloned and expanded in the presence of anti‐IL4 + anti‐IL‐4R mAb produced much lower levels of IL‐4 and IL‐5. It is concluded that almost every single naive human CD4 T cell primed and expanded in the absence of exogenous IL‐4 releases sufficient autocrine IL‐4 to support its clonal expansion into high IL‐4/IL‐5 producers.