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Original Article |
Correspondence to: Tom H.M. Ottenhoff, Department of Immunohematology and Blood Transfusion, LUMC, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Tel:31-71-5265128 Fax:31-71-5216751 E-mail:t.h.m.ottenhoff{at}lumc.nl.
Genetic lack of interleukin 12 receptor ß1 (IL-12Rß1) surface expression predisposes to severe infections by poorly pathogenic mycobacteria or Salmonella and causes strongly decreased, but not completely abrogated, interferon (IFN)-
production. To study IL-12Rß1–independent residual IFN- production, we have generated mycobacterium–specific T cell clones (TCCs) from IL-12Rß1–deficient individuals. All TCCs displayed a T helper type 1 phenotype and the majority responded to IL-12 by increased IFN- production and proliferative responses upon activation. This response to IL-12 could be further augmented by exogenous IL-18. IL-12Rß2 was found to be normally expressed in the absence of IL-12Rß1, and could be upregulated by IFN-
. Expression of IL-12Rß2 alone, however, was insufficient to induce signal transducer and activator of transcription (Stat)4 activation in response to IL-12, whereas IFN-/IFN-R ligation resulted in Stat4 activation in both control and IL-12Rß1–deficient cells. IL-12 failed to upregulate cell surface expression of IL-18R, integrin 6, and IL-12Rß2 on IL-12Rß1–deficient cells, whereas this was normal on control cells. IL-12–induced IFN- production in IL-12Rß1–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-12Rß1. Moreover, the results reveal the presence of a novel IL-12Rß1/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-12Rß1 deficiency.
Key Words:
mycobacteria, Th1, interleukin 12 (receptor), interleukin 18 (receptor), interferon-
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