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Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
Cytokines are central regulatory elements in peripheral lymphocyte
differentiation, but their role in T cell ontogeny is poorly defined.
In the present study, we evaluated the role of IL-12 in thymocyte
selection more directly by determining its role in two models of in
vivo negative selection. In initial studies we demonstrated that
abundant intrathymic IL-12 synthesis occurs during OVA peptide-induced
negative selection of thymocytes in neonatal OVA-TCR transgenic mice,
and such synthesis is associated with increased IL-12R ß2-chain
expression as well as STAT4 intracellular signaling. In further
studies, we showed that this form of negative selection was occurring
at the 
ßTCRlowCD4lowCD8low
stage and was prevented by the coadministration of anti-IL-12. In
addition, the IL-12-dependent thymocyte depletion was occurring through
an intrathymic apoptosis mechanism, also prevented by administration of
anti-IL-12. Finally, we showed that IL-12 p40-/- mice
displayed aberrant negative selection of double positive
CD4+CD8+ thymocytes when injected with
anti-CD3 mAb. These studies suggest that intact intrathymic IL-12
production is necessary for the negative selection of thymocytes
occurring in relation to a high "self" Ag load, possible through
its ability to induce the thymocyte maturation and cytokine production
necessary for such selection.
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