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Division of Immunochemistry, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
The involvement of specific accessory/costimulatory molecules in
differentiation to Th1 and Th2 phenotypes is controversial. Reports
suggest that molecules such as CD4, CD28, and Ox-40 support Th2
differentiation and suppress Th1 differentiation, whereas others such
as LFA-1 support Th1 responses and suppress Th2 responses. We have
previously defined an in vitro model of differentiation that is
absolutely dependent on the initial dose and affinity of peptide
presented to a naive CD4 cell. The dose and affinity of Ag regulate
autocrine production of IL-2, IL-4, and IFN-
, which in turn govern
differentiation to Th1 and Th2 phenotypes. We have used this system to
confirm that CD4, CD28, and Ox-40 interactions can promote, and LFA-1
interactions can suppress, differentiation of cells secreting the Th2
cytokines IL-5 and IL-13. However, for CD4 and LFA-1, this is only seen
over a certain range of peptide doses. In addition, CD28 and Ox-40
interactions also promote Th1 differentiation. In general, agonist Abs
to accessory molecules shifted the response curves for IFN-, IL-5,
and IL-13 to lower doses, whereas antagonist reagents resulted in
similar curves shifted toward the higher doses. We conclude that
ligation of cell surface accessory receptors enables low doses of Ag to
promote responses normally induced only by higher doses. Individual
receptors do not intrinsically regulate one cytokine phenotype or
another, suggesting that differentiation is controlled by the level of
expression of multiple accessory molecule pairs integrated with the
number and affinity of peptide/MHC complexes.
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