Persistent lentivirus infection induces early myeloid suppressor cells expansion to subvert protective memory CD8 T cell response✰,✰✰

EBioMedicine

Jie Peng¹  Qingqing Lin²  Kang Liu³  Hangying Tang³  Kenji Nishiura³  Jianguo Liang³  Kwok-Yung Yuen³  Zhiwu Tan³  Zhiwei Chen³  Li Liu³  Kayi Kwan³  Jiaze Sun³  Jun Fang³  Hauyee Kwok³  Zhenglong Du³  Hui Wang⁴ 

[1] Corresponding authors: Li Liu, Ph.D., Hui Wang, M.D. and Zhiwei Chen, Ph.D., AIDS Institute and Department of Microbiology, State Key Laboratory of Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong S.A.R., P.R. China.;HKU-AIDS Institute Shenzhen Research Laboratory and AIDS Clinical Research Laboratory, Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Key Clinical Department of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, P.R. China;AIDS Institute and Department of Microbiology, State Key Laboratory of Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong SAR, P.R. China;Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, United States;

关键词: Persistent virus infection;    Vaccine;    Memory cd8 t cell response;    MDSCs;    T cell exhaustion;   

DOI  :  

来源: DOAJ

【 摘 要 】

Background: Memory CD8+ T cell responses play an essential role in protection against persistent infection. However, HIV-1 evades vaccine-induced memory CD8+ T cell response by mechanisms that are not fully understood. Methods: We analyzed the temporal dynamics of CD8+ T cell recall activity and function during EcoHIV infection in a potent PD1-based vaccine immunized immunocompetent mice. Findings: Upon intraperitoneal EcoHIV infection, high levels of HIV-1 GAG-specific CD8+ T lymphocytes recall response reduced EcoHIV-infected cells significantly. However, this protective effect diminished quickly after seven days, followed by a rapid reduction of GAG-specific CD8+ T cell number and activity, and viral persistence. Mechanistically, EcoHIV activated dendritic cells (DCs) and myeloid cells. Myeloid cells were infected and rapidly expanded, exhibiting elevated PD-L1/-L2 expression and T cell suppressive function before day 7, and were resistant to CD8+ T cell-mediated apoptosis. Depletion of myeloid-derived suppressor cells (MDSCs) reduced EcoHIV infection and boosted T cell responses. Interpretation: This study provides an overview of the temporal interplay of persistent virus, DCs, MDSCs and antigen-specific CD8+ T cells during acute infection. We identify MDSCs as critical gatekeepers that restrain antiviral T cell memory responses, and highlight MDSCs as an important target for developing effective vaccines against chronic human infections. Funding: Hong Kong Research Grant Council (T11–709/18-N, HKU5/CRF/13G), General Research Fund (17122915 and 17114114), Hong Kong Health and Medical Research Fund (11100752, 14130582, 16150662), Grant RGC-ANR A-HKU709/14, the San-Ming Project of Medicine (SZSM201512029), University Development Fund of the University of Hong Kong and Li Ka Shing Faculty of Medicine Matching Fund to HKU AIDS Institute.

【 授权许可】

Unknown