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from Human Peripheral Blood Mononuclear Cells in an IL-12- and/or CD28-Dependent Manner
*
Lymphokine Regulation Unit, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, and
Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
The Henry M. Jackson Foundation for the Advancement of Military Medicine, U.S. Military HIV Research Program, Bethesda, MD 20889; and
§
Immunex Corp., Seattle, WA 98191
CD40 ligand (CD40L)/CD40 costimulation is an important regulator of
Th1 responses. Two mechanisms by which CD40L/CD40 stimulation may
enhance IFN-
are via direct induction of IL-12 and augmentation of
the expression of costimulatory molecules such as B7 from APCs. We
examined the ability of CD40L/CD40 stimulation to regulate the
production of IFN- through IL-12 and/or CD28 costimulation from
human PBMCs stimulated with T cell-specific stimuli. The roles of
exogenous and endogenous CD40L/CD40 stimulation were evaluated using a
trimeric soluble CD40L agonist (CD40T) and an anti-CD40L Ab,
respectively. The presence of CD40T in cultures increased the
production of IL-12 and IFN- from PBMCs stimulated with varying
amounts of PHA. The mechanism, however, by which CD40T enhanced IFN-
varied according to the level of T cell activation. Under maximal
stimulatory conditions (PHA, 1/100), an IL-12-dependent pathway was
dominant. At relatively low levels of T cell stimulation (PHA, 1/500
and 1/1000), however, an additional IL-12-independent CD28-dependent
pathway was elucidated. We further studied the role of exogenous CD28
stimulation in regulating the production of IFN-. The enhancement of
IFN- production induced by direct CD28 stimulation was primarily
dependent on endogenous IL-12 or CD40L/CD40 stimulation. Together,
these data suggest that the production of IFN- involves a complex
interaction between two interdependent, yet distinct, costimulatory
pathways and provide evidence that CD40T may be an effective adjuvant
for the enhancement of responses.
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