Residual Type 1 Immunity in Patients Genetically Deficient for Interleukin 12 Receptor β1 (IL-12Rβ1)

• Published in: The Journal of experimental medicine Vol. 192; no. 4; pp. 517 - 528
• Main Authors: Verhagen, Claudia E., de Boer, Tjitske, Smits, Hermelijn H., Verreck, Frank A.W., Wierenga, Eddy A., Kurimoto, M., Lammas, D. Anthony, Kumararatne, Dinakanthe S., Sanal, Ozden, Kroon, Frank P., van Dissel, Jaap T., Sinigaglia, Francesco, Ottenhoff, Tom H.M.
• Format: Journal Article
• Language: English
• Published: 21.08.2000
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.192.4.517

Genetic lack of interleukin 12 receptor β1 (IL-12Rβ1) surface expression predisposes to severe infections by poorly pathogenic mycobacteria or Salmonella and causes strongly decreased, but not completely abrogated, interferon (IFN)-γ production. To study IL-12Rβ1–independent residual IFN-γ production, we have generated mycobacterium–specific T cell clones (TCCs) from IL-12Rβ1–deficient individuals. All TCCs displayed a T helper type 1 phenotype and the majority responded to IL-12 by increased IFN-γ production and proliferative responses upon activation. This response to IL-12 could be further augmented by exogenous IL-18. IL-12Rβ2 was found to be normally expressed in the absence of IL-12Rβ1, and could be upregulated by IFN-α. Expression of IL-12Rβ2 alone, however, was insufficient to induce signal transducer and activator of transcription (Stat)4 activation in response to IL-12, whereas IFN-α/IFN-αR ligation resulted in Stat4 activation in both control and IL-12Rβ1–deficient cells. IL-12 failed to upregulate cell surface expression of IL-18R, integrin α6, and IL-12Rβ2 on IL-12Rβ1–deficient cells, whereas this was normal on control cells. IL-12–induced IFN-γ production in IL-12Rβ1–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. Collectively, these results indicate that IL-12 acts as a partial agonist in the absence of IL-12Rβ1. Moreover, the results reveal the presence of a novel IL-12Rβ1/Stat4–independent pathway of IL-12 responsiveness in activated human T cells involving MAP kinases. This pathway is likely to play a role in the residual type 1 immunity in IL-12Rβ1 deficiency.