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Division of Immunochemistry, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
Opposing viewpoints exist regarding how Ag dose and affinity
modulate Th1/Th2 differentiation, with data suggesting that both high
and low level stimulation favors Th2 responses. With transgenic T cells
bearing a single TCR, we present novel data, using peptides differing
in affinity for the TCR, that show that the time period of
differentiation can determine whether Th1 or Th2 responses predominate
as the level of initial stimulation is altered. Over the short term,
IFN-
-producing cells were induced by lower levels of stimulation
than IL-4-producing cells, although optimal induction of both was seen
with the same high level of stimulation. Over the long term, however,
high doses of high affinity peptides led selectively to
IFN--secreting cells, whereas IL-4- and IL-5-secreting cells
predominated with lower levels of initial signaling, brought about by
moderate doses of high affinity peptides. In contrast, too low a level
of stimulation at the naive T cell stage, with low affinity peptides at
any concentration, promoted only IL-2-secreting effectors or was not
sufficient for long term T cell survival. These results demonstrate
that the level of signaling achieved through the TCR is intimately
associated with the induction of distinct cytokine-secreting T cells.
We show that dose, affinity, time over which differentiation occurs,
and initial production of IL-4 and IFN- all can contribute to which
T cell subset will predominate. Furthermore, these data reconcile the
two opposing views on the effects of dose and affinity and provide a
unifying model of Th1/Th2 differentiation based on strength of
signaling and length of response.
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