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1
La Jolla Institute for Allergy and Immunology, Division of Immunochemistry, San Diego, CA 92121
Many studies have classified CD4 responses into either Th1-like or
Th2-like, based on cytokine secretion profiles, but little significance
has been placed on Th0 cells. This has largely resulted from studies
that suggested that Th0 populations primarily comprise individual Th1
and Th2 cells. Here, we show that priming of Ag-specific naive CD4
cells with moderate dose IL-4 generates a Th0 population that is
evident after 3 days in vitro and becomes prevalent after successive
encounters with Ag over a 9-day period. By intracellular cytokine
staining, the majority (>60%) of effector cells generated in this way
produce either IL-4, IFN-
and IL-2, or IL-4 and IFN- without
IL-2. Endogenous IFN- secreted over the initial 3 days of culture
was critical for generating Th0 cells, since neutralization allowed
IL-4 to induce differentiation into Th2-like cells. Successive
encounters with Ag were required for generating Th0 cells, and their
stability and persistence were governed by the balance of endogenous
IL-4 and IFN- secreted during the later stages of differentiation.
Studies blocking Fas-induced cell death showed that this process played
no role in Th0 cell generation, and differential death of committed Th1
or Th2 cells was not required for Th0 persistence. These data suggest
that Th0 cells can be as prevalent as Th1- or Th2-like cells after
naive CD4 activation, that the relative levels of autocrine IL-4 and
IFN- are important to the lack of commitment, and that not all cells
are predestined to the Th1 or Th2 phenotypes early in the response.
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