A role for IL-12 receptor expression and signal transduction in host defense in leprosy.
The generation of cell-mediated immunity against intracellular infection involves the production of IL-12, a critical cytokine required for the development of Th1 responses. The biologic activities of IL-12 are mediated through a specific, high affinity IL-12R composed of an IL-12Rbeta1/IL-12Rbeta2 heterodimer, with the IL-12Rbeta2 chain involved in signaling via Stat4. We investigated IL-12R expression and function in human infectious disease, using the clinical/immunologic spectrum of leprosy as a model. T cells from tuberculoid patients, the resistant form of leprosy, are responsive to IL-12; however, T cells from lepromatous patients, the susceptible form of leprosy, do not respond to IL-12. We found that the IL-12Rbeta2 was more highly expressed in tuberculoid lesions compared with lepromatous lesions. In contrast, IL-12Rbeta1 expression was similar in both tuberculoid and lepromatous lesions. The expression of IL-12Rbeta2 on T cells was up-regulated by Mycobacterium leprae in tuberculoid but not in lepromatous patients. Furthermore, IL-12 induced Stat4 phosphorylation and DNA binding in M. leprae-activated T cells from tuberculoid but not from lepromatous patients. Interestingly, IL-12Rbeta2 in lepromatous patients could be up-regulated by stimulation with M. tuberculosis. These data suggest that Th response to M. leprae determines IL-12Rbeta2 expression and function in host defense in leprosy.
Kim
J
J
Division of Dermatology, University of California School of Medicine, Los Angeles, CA 90095, USA.
Uyemura
K
K
Van Dyke
M K
MK
Legaspi
A J
AJ
Rea
T H
TH
Shuai
K
K
Modlin
R L
RL
D000942:Antigens, Bacterial / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000378:metabolism / Q000502:physiology*; D015440:Leprosy, Lepromatous / Q000276:immunology*; D015441:Leprosy, Tuberculoid / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D009166:Mycobacterium leprae / Q000276:immunology; D010766:Phosphorylation; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000502:physiology*; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism
D000942:Antigens, Bacterial; D004268:DNA-Binding Proteins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma