Thymosin alpha 1 (Tα1) reduces the mortality of severe COVID-19 by restoration of lymphocytopenia and reversion of exhausted T cells

Liu, Yueping; Pang, Yue; Hu, Zhenhong; Wu, Ming; Wang, Chenhui; Feng, Zeqing; Mao, Congzheng; Tan, Yingjun; Liu, Ying; Chen, Li; Li, Min; Wang, Gang; Yuan, Zilin; Diao, Bo; Wu, Yuzhang; Chen, Yongwen

BACKGROUND: We previously reported that lymphocytopenia and T cell exhaustion is notable in acute COVID19 patients, especially in aged and severe cases. Thymosin alpha 1 (Tα1) had been used in the treatment of viral infections as an immune response modifier for many years. However, clinical benefits and mechanism of Tα1 supplement to COVID-19 are still unclear. METHODS: We retrospectively reviewed the clinical outcomes of 76 severe cases with COVID-19 admitted into two hospitals in Wuhan from December 2019 to March 2020. The thymus output in peripheral blood mononuclear cells (PBMCs) from COVID-19 patients was measured by T cell receptor excision circles (TREC). The levels of T cell exhaustion markers PD-1 and Tim-3 on CD8(+) T cells were detected by flow cytometry. RESULTS: Compared with untreated group, Tα1 treatment significantly reduces mortality of severe COVID-19 patients (11.11% vs. 30.00%, p=0.044). Tα1 timely enhances blood T cell numbers in COVID-19 patients with severe lymphocytopenia (the counts of CD8(+) T cells or CD4(+ )T cells in circulation lower than 400/μL or 650/μL, respectively). Under such conditions, Tα1 also successfully restores CD8(+) and CD4(+) T cell numbers in aged patients. Meanwhile, Tα1 reduces PD-1 and Tim-3 expression on CD8(+) T cells from severe COVID-19 patients in comparison with untreated cases. It is of note that restoration of lymphocytopenia and acute exhaustion of T cells are roughly parallel to the rise of TRECs. CONCLUSIONS: Tα1 supplement significantly reduce mortality of severe COVID-19 patients. COVID-19 patients with the counts of CD8(+) T cells or CD4(+) T cells in circulation lower than 400/μL or 650/μL, respectively, gain more benefits from Tα1. Tα1 reverses T cell exhaustion and recovers immune reconstitution through promoting thymus output during SARS-CoV-2 infection.