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and CD40 Ligand Expression in Human T Cells: Disruption of Both IL-12-Dependent and -Independent Pathways of IFN- Production
* Laboratory of Immunology, National Eye Institute,
Critical Care Medicine Department, Clinical Center, and
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
Guy’s, King’s, and St. Thomas’ Hospital, London, United Kingdom.
mAbs directed against the 
-chain (Tac/CD25) of the IL-2R are an
emerging therapy in both transplantation and autoimmune disease.
However, the mechanisms underlying their therapeutic efficacy have not
been fully elucidated. Therefore, we examined the affect of IL-2R
blockade on Th1 and Th2 cytokine production from human PBMC. Addition
of a humanized anti-Tac Ab (HAT) to activated PBMC cultures
inhibited IFN-
production from CD4 and CD8 T cells by 80–90%. HAT
partially inhibited production of TNF- and completely inhibited
production of IL-4, IL-5, and IL-10. Furthermore, IL-12, a central
regulatory cytokine that induces IFN-, was undetectable in treated
cultures. As T cell-dependent induction of IL-12 is regulated via
CD40/CD40 ligand (CD40L) interactions, we examined the affect of
HAT on CD40L expression. We found CD40L expression to be biphasic with
an early (6 h) peak that is CD28/IL-2-independent, but a later peak (48
h) being CD28/IL-2-dependent and inhibited by HAT. Similarly, IFN-
production at 6 h was CD28/IL-2-independent but
CD28/IL-2-dependent and inhibited by HAT at 48 h. Nonetheless,
addition of rCD40L or exogenous IL-12 to HAT-treated cultures could not
restore IFN- production. The IFN- deficit in such cultures
appears to be due to a direct inhibition by HAT of IL-12-independent
IFN- production from T cells rather than altered expression of
either the IL-12R
1 or IL-12R2 chains. These data demonstrate that
IL-2 plays a critical role in the regulation of Th1 and Th2 responses
and impacts both IL-12-dependent and -independent IFN- production.
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