Zhang Xin, Lu Xiaofan, Cheung Allen Ka Loon, Zhang Qiuyue, Liu Zhiying, Li Zhen, Yuan Lin, Wang Rui, Liu Yan, Tang Bin, Xia Huan, Wu Hao, Zhang Tong, Su Bin
Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China.
Beijing Key Laboratory for HIV/AIDS Research, Beijing, China.
Front Immunol. 2021 Feb 26;12:602492. doi: 10.3389/fimmu.2021.602492. eCollection 2021.
TIGIT expression on natural killer (NK) cells is associated with dysfunction during chronic HIV infection, but the phenotype and biological functions of these cells in the context of acute HIV-1 infection remain poorly understood. Here, 19 acutely infected HIV-1 patients traced at first, third and twelfth month, and age-matched patients with chronic HIV-1 infection were enrolled to investigate the phenotype and functions of TIGIT expression on NK cells. We found that TIGIT-expressing NK cells did not increase in frequency in the first, third and twelfth month of infection until chronic HIV-1 infection lasted over 2 years. The number of TIGITNK cells in acute infection was positively associated with HIV-1 viral load ( = 0.53, = 0.0009). CD96 was significantly upregulated on NK cells after acute infection for 1 month and in chronic infection over 2 years, while CD226 was downregulated in chronic infection over 2 years. Further, at different stages of infection, CD96CD226 cells diminished among total NK cells, TIGITNK and TIGITNK cells, while CD96CD226 cells expanded. Reduced CD96CD226 cells and elevated CD96CD226 cells among NK cells especially TIGITNK cells, had opposite associations with viral load in the first month of infection, as well as CD4 T-cell counts in including the twelfth month and more than 2 years of chronic infection. In both HIV-1-infected individuals and healthy donors, TIGIT was predominantly expressed in NKG2ANKG2CNK cells, with a significantly higher proportion than in NKG2ANKG2CNK cells. Moreover, the frequencies of TIGITNK cells were positively associated with the frequencies of NKG2ANKG2CNK cells in acute infection ( = 0.62, < 0.0001), chronic infection ( = 0.37, = 0.023) and healthy donors ( = 0.36, = 0.020). Enhanced early activation and coexpression of CD38 and HLA-DR in TIGITNK cells were detected compared to TIGITNK cells, both of which were inversely associated with the decrease in CD4 T-cell counts in both acute and chronic HIV-1 infection. The ability of TIGITNK cells to produce TNF-α, IFN-γ and CD107a degranulation substance were consistently weaker than that of TIGITNK cells in both acute and chronic infection. Moreover, the functionalities of TIGITNK cells were lower than those of TIGITNK cells, except for TNF-αCD107aIFN-γNK cells. These findings highlight the phenotype and functional characteristics of TIGIT-expressing NK cells which have poor capabilities in inhibiting HIV-1 replication and maintaining CD4 T-cell counts.
自然杀伤（NK）细胞上TIGIT的表达与慢性HIV感染期间的功能障碍有关，但在急性HIV-1感染情况下这些细胞的表型和生物学功能仍知之甚少。在此，招募了19例在第1、3和12个月进行追踪的急性HIV-1感染患者以及年龄匹配的慢性HIV-1感染患者，以研究NK细胞上TIGIT表达的表型和功能。我们发现，在感染的第1、3和12个月，表达TIGIT的NK细胞频率并未增加，直到慢性HIV-1感染持续超过2年。急性感染中TIGIT⁺NK细胞的数量与HIV-1病毒载量呈正相关（r = 0.53，P = 0.0009）。急性感染1个月后以及慢性感染超过2年时，NK细胞上的CD96显著上调，而慢性感染超过2年时CD226下调。此外，在感染的不同阶段，CD96⁺CD226⁻细胞在总NK细胞、TIGIT⁺NK和TIGIT⁻NK细胞中减少，而CD96⁻CD226⁺细胞增多。NK细胞尤其是TIGIT⁺NK细胞中CD96⁺CD226⁻细胞减少和CD96⁻CD226⁺细胞增多，在感染的第1个月与病毒载量以及在包括第12个月和慢性感染超过2年时的CD4⁺T细胞计数呈相反关系。在HIV-1感染个体和健康供体中，TIGIT主要在NKG2A⁺NKG2C⁻NK细胞中表达，其比例显著高于NKG2A⁻NKG2C⁺NK细胞。此外，急性感染（r = 0.62，P < 0.0001）、慢性感染（r = 0.37，P = 0.023）和健康供体（r = 0.36，P = 0.020）中，TIGIT⁺NK细胞的频率与NKG2A⁺NKG2C⁻NK细胞的频率呈正相关。与TIGIT⁻NK细胞相比，检测到TIGIT⁺NK细胞中CD38和HLA-DR的早期激活和共表达增强，这两者在急性和慢性HIV-1感染中均与CD4⁺T细胞计数的减少呈负相关。在急性和慢性感染中，TIGIT⁺NK细胞产生TNF-α、IFN-γ和CD107a脱颗粒物质的能力始终弱于TIGIT⁻NK细胞。此外，除了TNF-α⁺CD107a⁺IFN-γ⁺NK细胞外，TIGIT⁺NK细胞的功能低于TIGIT⁻NK细胞。这些发现突出了表达TIGIT的NK细胞的表型和功能特征，其在抑制HIV-1复制和维持CD4⁺T细胞计数方面能力较差。
