Mutations in the zinc finger of
I kappa B kinase gamma (
IKK gamma) are associated with
hypohidrotic ectodermal dysplasia-immune deficiency (
HED-ID) in which the major immune deficit is the inability to switch Ab heavy chain class. However, the pathophysiologic role of the mutations has not been fully delineated. Since help from activated Th cells is essential in Ab class switching, we sought to examine how these mutations affect T cell activation. Using a human T cell line that was null for
IKK gamma, we generated cells stably expressing two of the reported mutations, namely, D406V and C417R. Cells expressing either mutation failed to induce
IL-2 following stimulation with PMA/
ionomycin while the induction of
IL-2 was restored in cells reconstituted with the wild type
IKK gamma. The lack of
IL-2 upregulation correlated with the lack of
NF-kappaB activation as evidenced by the inability to induce
I kappa B alpha degradation,
NF-kappaB binding to
DNA and the expression of a reporter gene. However, both mutations did not prevent the incorporation of
IKK gamma into the IKK complex and, interestingly, the induced phosphorylation of
I kappa B alpha at S32 and S36 and its subsequent ubiquitination were not affected. The suppression of
IL-2 induction was solely due to the inhibition of
NF-kappaB activation as the mutations did not impair the activation of
AP-1 and NFAT. Our data indicated that the failure of T cells to undergo activation in response to TCR stimuli may play a role in the pathophysiology of
HED-ID and also showed that
IKK gamma has a role in the post-ubiquitination processing of
I kappa B alpha.