CTLA-4 engagement regulates NF-ΚB activation in vivo

Abstract

CTLA-4 engagement inhibits TCR-dependent functions and CTLA-4-/- mice develop a lymphoproliferative disorder leading to early lethality. In vitro, ligation of CTLA-4 reduces TCR-mediated activation of NF-κB, a transcription factor implicated in promoting T cell survival and cytokine production. However, whether NF-κB inhibition downstream of CTLA-4 is necessary for down-regulation of T cell responses is not known. We hypothesized that signaling pathways that are antagonized when CTLA-4 is engaged should be augmented when CTLA-4 is absent and found that spontaneous NF-κB activity was increased in T cells from CTLA-4-/- mice. To determine the importance of NF-κB inhibition upon CTLA-4 engagement in vivo, CTLA-4-/- mice were interbred with mice expressing a transdominant IκBα mutant under the control of the Lck promoter. The resulting mice had reduced spontaneous NF-κB activity in T cells, delayed mortality, and reduced leukocytic accumulation in spleen, lymph nodes, and exocrine pancreas as compared with CTLA-4-/- littermates. However, impaired NF-κB activation in T cells did not prevent the up-regulation of activation markers on T cells or the acquisition of effector cytokine production. Thus, impaired NF-κB activity in T cells prevents specific aspects of the CTLA-4-/- phenotype, suggesting that inhibition of NF-κB activation is one of the key biochemical events regulated by CTLA-4 ligation in vivo.