Impairment of STAT activation by IL-12 in a patient with atypical mycobacterial and staphylococcal infections

IL-12 plays a pivotal role in the stimulation of immune responses against i ntracellular infections. This role is manifested in the increased susceptib ility to atypical mycobacterial and salmonella infections among individuals whose lymphocytes lack expression of IL-12R beta 1. Here, we report on a p atient with Mycobacterium avium infection, recurrent Staphylococcus aureus sinusitis, and multiple adverse drug reactions whose T cells were unable to produce IFN-gamma or proliferate in response to IL-12 despite the expressi on of wild-type IL-12R beta 1 and IL-12R beta 2. The defect in these functi onal responses to IL-12 was selective, as cytolytic activity induced by IL- 12 was intact, and lymphocytes were responsive to stimulation by IL-2. An e xamination of cytokine signaling revealed that STAT4 and extracellular regu lated kinase 1 (ERK1) activation by IL-12 was intact, whereas the activatio n of STAT1, -3, and -5 by IL-12 was lost. This impairment of STAT activatio n was specific for IL-12, as STAT activation by IL-2, IL-15, and IFN-gamma was unaffected. These findings demonstrate that the activation of STAT4 alo ne is not sufficient for IL-12-induced IFN-gamma production and proliferati on and suggest that other STATs play a role in these responses to IL-12. Wh ile the etiology of the impaired IL-12 signaling in this patient has not ye t been elucidated, the absence of mutations in IL-12R beta 1 or IL-12R beta 2 and the preservation of STAT4 activation raise the possibility that ther e may be a mutation in an as yet undiscovered component of the IL-12 signal ing complex that is normally required for the recruitment and activation of STAT1, -3, and -5.