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Programmed death-1 (PD-1)-dependent functional impairment of CD4+ T cells in recurrent genital papilloma
Authors:Dong-Yeop Chang  Sang Hoon Song  Sooseong You  Jino Lee  Jihye Kim  Vito Racanelli  Hwancheol Son  Eui-Cheol Shin
Institution:1. Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, 291 Daehak-ro, Daejeon, 305-701, Republic of Korea
2. Department of Otorhinolaryngology, Gyeongsang National University Hospital, Jinju, Republic of Korea
3. Department of Urology, Asan Medical Center, Seoul, Republic of Korea
4. Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
5. Department of Urology, Boramae Medical Center, Seoul National University College of Medicine, 20, Boramae-ro 5-Gil Dongjak-gu, Seoul, 156-707, Republic of Korea
Abstract:Genital papilloma is caused by human papilloma virus (HPV) infection and recurs frequently. Although T cells are known to play a critical role in the control of HPV infection and papilloma development, the function and phenotype of these cells in the lesion remain to be elucidated. In the present study, we examined the function and phenotype of CD4+ T cells isolated from the lesions of primary (n = 9) and recurrent (n = 11) genital papillomas. In recurrent papillomas, the frequency of proliferating (Ki-67+) CD4+ T cells was significantly reduced compared with primary papillomas. Cytokine production was evaluated by intracellular cytokine staining in anti-CD3/anti-CD28-stimulated CD4+ T cells. CD4+ T cells from recurrent lesions showed impaired production of IL-2, IFN-γ, and TNF-α. Of interest, the frequency of cytokine-producing CD4+ T cells significantly correlated with the frequency of Ki-67+CD4+ T cells. We also studied expression of programmed death-1 (PD-1), a T-cell exhaustion marker. The frequency of PD-1+CD4+ T cells was significantly increased in recurrent lesions and inversely correlated with the frequency of cytokine-producing CD4+ T cells. The functional significance of PD-1 expression was determined in blocking assays with anti-PD-L1, which restored cytokine production of CD4+ T cells from recurrent lesions. Taken together, in recurrent genital papilloma lesions, proliferation, and cytokine production by CD4+ T cells are impaired and the PD-1/PD-L1 interaction is responsible for the functional impairment of CD4+ T cells.
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