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Cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibits CD28-induced IκBα degradation and RelA activation

1999; Wiley; Volume: 29; Issue: 3 Linguagem: Inglês

10.1002/(sici)1521-4141(199903)29

1521-4141

Claudio Pioli, Lucia Gatta, Daniela Frasca, Gino Doria,

Immune Cell Function and Interaction

Purified CD4+ cells from the spleens of C57BL/6 mice were stimulated with anti-CD3, anti-CD28 and anti-cytotoxic T lymphocyte antigen (CTLA)-4 monoclonal antibodies. The results show that CTLA-4 stimulation inhibits IL-2 production induced by CD3-CD28 co-stimulation. Since CD3-CD28 co-stimulation induces IkappaBalpha degradation and consequently activates RelA, an NFkappaB family member relevant for the induction of IL-2 mRNA transcription, we tested whether the inhibitory effect of CTLA-4 stimulation interferes with this mechanism. CD3-CD28 co-stimulation was found to induce a drastic decrease in cytoplasmic IkappaBalpha and increase in nuclear RelA. CTLA-4 stimulation abrogates this effect of co-stimulation by increasing the level of cytoplasmic IkappaBalpha and decreasing the nuclear RelA level and DNA-binding activity. In conclusion, our results indicate that the inhibitory effect of CTLA-4 engagement on cytokine production correlates with prevention of IkappaBalpha degradation and inhibition of RelA nuclear translocation.