title: CD4+IL-21+T cells are correlated with regulatory T cells and IL-21 promotes regulatory T cells survival during HIV infection.
abstract: 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.
  
  
  
  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+CD127lowTregs' 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.
  
  
  
  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+CD127lowTregs. 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.
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Zi-Ning
authors.initials: ZN
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Bai
authors.affiliation: 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.
authors.forename: Ya-Jing
authors.initials: YJ
authors.lastname: Fu
authors.affiliation: 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.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Hong
authors.initials: H
authors.lastname: Shang
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007378:Interleukins / Q000276:immunology*; D008297:Male; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D060908:CTLA-4 Antigen; D007378:Interleukins; D016212:Transforming Growth Factor beta; D000098546:Interleukin-21
keywords: HIV; IL-21; Regulatory T cell