Genetic lack of interleukin 12 receptor beta 1 (IL-12R beta 1) surface expression predisposes to severe infections by poorly pathogenic mycobacteria or Salmonella and causes strongly decreased, but not completely abrogated, interferon (IFN)-gamma production. To study IL-12R beta 1-independent residual IFN-gamma production, we have generated mycobacterium-specific T cell clones (TCCs) from IL-12R beta 1-deficient individuals. All TCCs displayed a T helper type 1 phenotype and the majority responded to IL-12 by increased IFN-gamma production and proliferative responses upon activation. This response to IL-12 could be further augmented by exogenous IL-18. IL-12R beta 2 was found to be: normally expressed in the absence of IL-12R beta 1, and could be upregulated by IFN-alpha. Expression of IL-12R beta 2 alone, however, was insufficient to induce signal transducer and activator of transcription (Stat)LF activation in response to IL-12, whereas IFN-alpha/IFN-alpha R ligation resulted in Stat4 activation in both control and IL-12R beta 1-deficient cells. IL-12 failed to upregulate cell surface expression of IL-18R, integrin alpha 6, and IL-12R beta 2 on IL-12R beta 2-deficient cells, whereas this was normal on control cells. IL-12-induced IFN-gamma production in IL-12R beta 1-deficient T cells could be inhibited by the p38 mitogen-activated protein kinase (MAP) kinase inhibitor SB203580 and the MAP kinase kinase (MEK) 1/2 inhibitor U0126, suggesting involvement of MAP kinases in this alternative, Stat4-independent, IL-12 signaling pathway.