The Journal of Experimental Medicine
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Published online 21 August 2000.
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© The Rockefeller University Press, 0022-1007/2000/8/517/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 4, August 21, 2000 517-528


Original Article

Residual Type 1 Immunity in Patients Genetically Deficient for Interleukin 12 Receptor β1 (IL-12Rβ1): Evidence for an IL-12Rβ1–Independent Pathway of IL-12 Responsiveness in Human T Cells



Claudia E. Verhagena, Tjitske de Boera, Hermelijn H. Smitsc, Frank A.W. Verrecka, Eddy A. Wierengac, M. Kurimotod, D. Anthony Lammase, Dinakanthe S. Kumararatnee, Ozden Sanalf, Frank P. Kroonb, Jaap T. van Disselb, Francesco Sinigagliag, and Tom H.M. Ottenhoffa

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


Abbreviations used in this paper: DTT, dithiothreitol; EMSA, electrophoretic mobility shift assay; ERK, extracellular signal–regulated kinase; JAK, Janus kinase; MAP, mitogen-activated protein; MAPK, MAP kinase; MEK, MAPK kinase; myc, mycobacterium; Stat, signal transducer and activator of transcription; TCC, T cell clone.

© 2000 The Rockefeller University Press


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