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Impairment of IL-12-Dependent STAT4 Nuclear Translocation in a Patient with Recurrent Mycobacterium avium Infection¹

Hidemi Toyoda^*,, Masaru Ido, Tatsuya Hayashi, Esteban C. Gabazza, Koji Suzuki, Jun Bu, Shigeki Tanaka, Takashi Nakano, Hitoshi Kamiya, James Chipeta^¶, Rodrick R. Kisenge^*, Jian Kang^*, Hiroki Hori^* and Yoshihiro Komada^2,*

Departments of ^* Pediatrics and Molecular Pathobiology, Mie University School of Medicine, Tsu, Mie, Japan; Department of Pediatrics, National Mie Central Hospital, Hisai, Mie, Japan; Department of Pediatrics, National Mie Hospital, Tsu, Mie, Japan; and ^¶ Department of Pediatrics and Child Health University Teaching Hospital, Lusaka, Zambia

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- and to proliferate in response to IL-12. Despite decreased expression of IL-12R 1 and 2 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-12R1, IL-12R2, STAT4, and STAT4-binding sequence of the IFN- 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- 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.

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