Zi-Ning Zhang1, Li-Xin Bai2, Ya-Jing Fu1, Yong-Jun Jiang1, Hong Shang3. 1. Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang, China. 2. Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, China. 3. Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang, China. Electronic address: hongshang100@hotmail.com.
Abstract
INTRODUCTION: IL-21 enhances T and natural killer cells survival and antiviral functions without promoting T cell activation during HIV infection, which makes it a better adjuvant in anti-HIV immunotherapy. Due to the pleiotropy and redundancy of cytokines, it is vital to have a comprehensive knowledge of the role of IL-21 in the regulation of immune responses. Regulatory T cells (Tregs) play an important role in immune regulation and are a determinant of immune therapeutic efficacy in certain circumstances. In this study, we explored the direct effect of IL-21 on Tregs during HIV infection, which has not been addressed before. METHODS: Thirty-four HIV treatment-naïve patients were enrolled and the relationship between CD4+IL-21+T cells and Tregs were studied. The effects of IL-21 on CD4+CD25+CD127low Tregs' apoptosis, proliferation, and CTLA-4 and TGF-β expression in HIV-infected patients was investigated and compared with the effect of other common γ-chain cytokines. RESULTS: We found the percentage and absolute numbers of CD4+IL-21+T cells were positively related to the frequency or absolute numbers of CD4+CD25+ or CD4+CD25+CD127low Tregs. Compared with the media-alone control, IL-21, IL-7, and IL-15 could significantly reduce apoptosis of Tregs (p<0.05). IL-21 did not promote the proliferation of Tregs as compared with media alone, while IL-2, IL-7, and IL-15 could significantly increase the proliferation of Tregs (p<0.05). IL-21 enhanced CTLA-4 expression by Tregs (p<0.05), but could not induce TGF-β secretion of Tregs from HIV infected patients. There were no significant differences of the fold induction of apoptosis, proliferation, or CTLA-4 and TGF-β expression by Tregs from HIV-infected patients and normal controls after IL-21 treatment. In vitro experiment showed that pretreatment with IL-21 significantly enhanced the suppressive effect of Tregs on CD8+ T cells' IFN-γ expression. CONCLUSION: We conclude that IL-21 promotes the survival and CTLA-4 expression of Tregs and enhanced the suppressive capacity of Tregs during HIV infection. These results broaden the understanding of HIV pathogenesis and provide critical information for HIV interventions. Copyright Â
INTRODUCTION:IL-21 enhances T and natural killer cells survival and antiviral functions without promoting T cell activation during HIV infection, which makes it a better adjuvant in anti-HIV immunotherapy. Due to the pleiotropy and redundancy of cytokines, it is vital to have a comprehensive knowledge of the role of IL-21 in the regulation of immune responses. Regulatory T cells (Tregs) play an important role in immune regulation and are a determinant of immune therapeutic efficacy in certain circumstances. In this study, we explored the direct effect of IL-21 on Tregs during HIV infection, which has not been addressed before. METHODS: Thirty-four HIV treatment-naïve patients were enrolled and the relationship between CD4+IL-21+T cells and Tregs were studied. The effects of IL-21 on CD4+CD25+CD127low Tregs' apoptosis, proliferation, and CTLA-4 and TGF-β expression in HIV-infectedpatients was investigated and compared with the effect of other common γ-chain cytokines. RESULTS: We found the percentage and absolute numbers of CD4+IL-21+T cells were positively related to the frequency or absolute numbers of CD4+CD25+ or CD4+CD25+CD127low Tregs. Compared with the media-alone control, IL-21, IL-7, and IL-15 could significantly reduce apoptosis of Tregs (p<0.05). IL-21 did not promote the proliferation of Tregs as compared with media alone, while IL-2, IL-7, and IL-15 could significantly increase the proliferation of Tregs (p<0.05). IL-21 enhanced CTLA-4 expression by Tregs (p<0.05), but could not induce TGF-β secretion of Tregs from HIV infectedpatients. There were no significant differences of the fold induction of apoptosis, proliferation, or CTLA-4 and TGF-β expression by Tregs from HIV-infectedpatients and normal controls after IL-21 treatment. In vitro experiment showed that pretreatment with IL-21 significantly enhanced the suppressive effect of Tregs on CD8+ T cells' IFN-γ expression. CONCLUSION: We conclude that IL-21 promotes the survival and CTLA-4 expression of Tregs and enhanced the suppressive capacity of Tregs during HIV infection. These results broaden the understanding of HIV pathogenesis and provide critical information for HIV interventions. Copyright Â