SJL mice produce little or no IgE in response to polyclonal stimulation with anti-IgD antibody and fail to express interleukin 4 (IL-4) mRNA in the spleen 5 days after injection of anti-IgD, in contrast to other mouse strains that produce substantial amounts of IgE and IL-4. Because IL-4 is critical in IgE production, the possibility that SJL mice are poor IgE producers because their naive T cells fail to differentiate into IL-4 producers must be seriously considered. IL-4 itself is the principal factor determining that naive T cells develop into IL-4 producers. A major source of IL-4 for such differentiation is a population of CD1-specific CD4+ T cells that express NK1.1. These cells produce IL-4 within 90 min of anti-CD3 injection. T cells from SJL mice fail to produce IL-4 in response to injection of anti-CD3. Similarly, SJL T cells and CD4+ thymocytes do not produce IL-4 in response to acute in vitro stimulation. SJL T cells show a marked deficiency in CD4+ cells that express the surface receptors associated with the NK1.1+ T-cell phenotype. This result indicates that the SJL defect in IgE and IL-4 production is associated with, and may be due to, the absence of the CD4+, NK1.1+ T-cell population.