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Original Article

Claudia E. Verhagen^a, Tjitske de Boer^a, Hermelijn H. Smits^c, Frank A.W. Verreck^a, Eddy A. Wierenga^c, M. Kurimoto^d, D. Anthony Lammas^e, Dinakanthe S. Kumararatne^e, Ozden Sanal^f, Frank P. Kroon^b, Jaap T. van Dissel^b, Francesco Sinigaglia^g, and Tom H.M. Ottenhoff^a

^a Department of Immunohematology and Blood Transfusion, 2300 RC Leiden University Medical Center (LUMC), 2300 RC, Leiden, The Netherlands
^b Department of Infectious Diseases, 2300 RC Leiden University Medical Center (LUMC), 2300 RC, Leiden, The Netherlands
^c The Department of Cell Biology and Histology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
^d The Fujisaki Institute, Hayashibara Biochemical Laboratories, Inc., 702-8006 Okayama, Japan
^e The Medical Research Council Centre for Immune Regulation, University of Birmingham, B9-555 Birmingham, United Kingdom
^f The Immunology Division, Hacettepe University Children's Hospital, 06100 Ankara, Turkey
^g Roche Milano Ricerche, I-20132 Milan, Italy
Department of Immunohematology and Blood Transfusion, LUMC, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands.31-71-521675131-71-5265128

t.h.m.ottenhoff{at}lumc.nl

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)- production. To study IL-12Rβ1–independent residual IFN- 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- 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-. 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-/IFN-R 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 6, and IL-12Rβ2 on IL-12Rβ1–deficient cells, whereas this was normal on control cells. IL-12–induced IFN- 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.

Key Words: mycobacteria • Th1 • interleukin 12 (receptor) • interleukin 18 (receptor) • interferon-

© 2000 The Rockefeller University Press

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