Impairment of IL-12-dependent STAT4 nuclear translocation in a patient with recurrent Mycobacterium avium infection.
We examined the immunological abnormality in a patient with recurrent Mycobacterium avium infection. T cells from the patient showed decreased ability both to produce IFN-gamma and to proliferate in response to IL-12. Despite decreased expression of IL-12R beta1 and beta2 chains in the patient's PHA-activated T cells, there was no difference in IL-12-induced tyrosine and serine phosphorylation of STAT4 in PHA-activated T cells between the patient and healthy subjects, suggesting that IL-12R signals are transmitted to STAT4 in the patient's PHA-activated T cells. Using EMSA, confocal laser microscopy, and Western blotting, we demonstrated that the nuclear translocation of STAT4 in response to IL-12 is reduced in PHA-activated T cells from the patient when compared with those from healthy subjects. Leptomycin B was used to examine whether nuclear export of STAT4 is increased in the patient's T cells. However, leptomycin B treatment did not reverse impaired IL-12-induced nuclear accumulation of STAT4. Although the exact mechanism responsible for the impaired STAT4 nuclear translocation in this patient remains unclear, the absence of mutation in the IL-12Rbeta1, IL-12Rbeta2, STAT4, and STAT4-binding sequence of the IFN-gamma gene and preservation of STAT4 tyrosine and serine phosphorylation suggest the existence of a defective STAT4 nuclear translocation. This defect is likely responsible for the impaired STAT4 nuclear translocation in IL-12-stimulated T cells, leading to impairment of both IFN-gamma production and cell proliferation. To the best of our knowledge, this is the first report of a patient with atypical mycobacterial infection associated with impairment of STAT4 nuclear translocation.
Department of Pediatrics, Mie University School of Medicine, Tsu, Mie, Japan.
Hidemi
H
Toyoda
Masaru
M
Ido
Tatsuya
T
Hayashi
Esteban C
EC
Gabazza
Koji
K
Suzuki
Jun
J
Bu
Shigeki
S
Tanaka
Takashi
T
Nakano
Hitoshi
H
Kamiya
James
J
Chipeta
Rodrick R
RR
Kisenge
Jian
J
Kang
Hiroki
H
Hori
Yoshihiro
Y
Komada
D021581:Active Transport, Cell Nucleus / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002467:Cell Nucleus / Q000276:immunology* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D007223:Infant; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000502:physiology*; D007700:Kinetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D018613:Microscopy, Confocal; D009162:Mycobacterium avium / Q000276:immunology*; D010766:Phosphorylation; D010835:Phytohemagglutinins / Q000494:pharmacology; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053707:Receptors, Interleukin-12; D012008:Recurrence; D050797:STAT4 Transcription Factor; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology
D004268:DNA-Binding Proteins; C508438:IL12RB1 protein, human; C508439:IL12RB2 protein, human; D010835:Phytohemagglutinins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators; D018664:Interleukin-12