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NF-B Regulates Expression of the MHC Class I-Related Chain A Gene in Activated T Lymphocytes¹

Luciana L. Molinero^*, Mercedes B. Fuertes^*, María Victoria Girart^*, Leonardo Fainboim^*, Gabriel A. Rabinovich^*, Mónica A. Costas and Norberto W. Zwirner^2,*

^* Laboratorio de Inmunogenética, Hospital de Clínicas "José de San Martín", and Departamento de Microbiología, Facultad de Medicina, Universidad de Buenos Aires (UBA), and Instituto de Investigaciones Médicas "Alfredo Lanari", Buenos Aires, Argentina

MHC class I-related chain A gene (MICA) is a stress-regulated, HLA-related molecule which exhibits a restricted pattern of expression. MICA protein is up-regulated on different tumor cells, and is recognized by the lectin-like NKG2D molecule expressed by cytotoxic T lymphocytes, CD8⁺ T lymphocytes, and NK cells. Although MICA is not expressed on resting lymphocytes, we demonstrated that it is induced on activated T cells. Because NF-B is actively involved in T cell activation, and is constitutively activated in many tumors, here we investigated whether NF-B may modulate MICA expression. Treatment with the NF-B inhibitor sulfasalazine (Sz) resulted in a dose-dependent inhibition of MICA expression in anti-CD3- and anti-CD28/PMA-activated T lymphocytes, as assessed by Western blot and RT-PCR analysis. Moreover, Sz also down-regulated MICA expression on epithelial tumor HeLa cells. MICA expression was accompanied by a Sz-sensitive IB degradation. EMSA with nuclear extracts from anti-CD3- and anti-CD28/PMA-stimulated T lymphocytes demonstrated the binding of a potential NF-B family transcription factor to a MICA gene intron 1-derived oligonucleotide that contains a putative B binding site. Supershift assays demonstrated the presence of p65(RelA)/p50 heterodimers and p50/p50 homodimers in the NF-B complexes bound to the B-MICA oligonucleotide. Transient transfection of HeLa cells with p65(RelA) up-regulated MICA expression, as assessed by Western blot and flow cytometry analysis. Hence, we conclude that NF-B regulates MICA expression on activated T lymphocytes and HeLa tumor cells, by binding to a specific sequence in the long intron 1 of the MICA gene. This constitutes the first description of a transcription factor that regulates MICA gene expression.

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