The most significant finding of this study was the low level of IL-2 in plasma and low expression of IL-2R in PBMC of critical patients, which may result in the remarkable decrease of CD8⁺ T cell and lymphocytes in critical patients with COVID-19 pneumonia. In addition, we found that total T cell, B cell, and NK cell counts were remarkably decreased in critical patients compared to normal controls.

At present, the rising epidemic situation in China has been effectively curbed through a series of preventive control and medical treatment. The new confirmed and suspected cases in China are basically cleared, and the treatment of remaining severe and critical cases has become the most important task. According to the latest guidelines for novel coronavirus pneumonia, the progressive decrease of peripheral blood lymphocytes is one of the clinical early warning indicators for adult patients with severe and critical illness. Similar to previous studies¹³, we also found that peripheral blood lymphocytes were decreased in the patients with COVID-19 pneumonia, especially in critical patients. Importantly, we found that CD8⁺ T cells were remarkably decreased, which was the same as another study¹⁴. Some studies have also shown that critical patients with COVID-19 pneumonia have an immune deficiency and hypoimmunity, which may also lead to serious infection and death¹⁵. Therefore, CD8⁺ T cell reduction may result in underlying increased mortality in critical patients.

The secretion of cytokines plays an important role in the development and differentiation of immune cells. Many studies have suggested that cytokine storms might be one of the causes of multiple organ failure and death in severe and critical patients with COVID-19 pneumonia^16,17. Similarly, our study also found that some inflammatory cytokines such as IL-6 and IL-10 increased in critical patients with COVID-19 pneumonia. Differently, we found that IL-2 was elevated in severe patients but decreased in critical patients with COVID-19 pneumonia. IL-2, also known as the T cell growth factor, is mainly produced by activated CD4⁺ T cells and CD8⁺ T cells^18,19,20,21. It has been demonstrated that IL-2 at high concentration enhances CD4⁺ T and CD8⁺ T cell activation by stimulating expansion and differentiation of conventional T cells and IL-2 at low concentration inhibits CD4⁺ T and CD8⁺ T cell activation by maintaining activity and survival of T regulatory cells (Treg)²¹. IL-2 is so specific and critical for T cells activation that we investigate the IL-2 signaling pathway. Consistent with IL-2 level in plasma, we found that the expression of IL-2R and JAK1-STAT5 in PBMC was decreased in critical patients with COVID-19 pneumonia. Therefore, the decrease of CD8⁺ T cells and lymphocytes in critical patients with COVID-19 pneumonia may be related to the inhibition of IL-2 signaling pathway.

In addition, we also observed that IL-10 and IL-6 was increased and IFN-γ was decreased in critical patients with COVID-19 pneumonia. Relative to IL-2, IL-10, IL-6, and IFN-γ have more versatile functions. IL-10 is considered a prototypical anti-inflammation cytokine²², but the recent findings indicate that high exogenous IL-10 level promotes the CD8⁺ T cell cytotoxicity and intermediate endogenous IL-10 level induces exhaustion of CD8⁺ T cells in tumor^23,24. IL-10 can inhibit IL-2 secretion and has heterogenity on CD8⁺ T cell activation which may depend on other environmental cytokines²⁴, so we speculate that it may take part in T cell activation through IL-2 pathway. IL-6 can induce the differentiation of T cells, whereas its level was increased in our study, so we think it plays an important role in secretion of acute phase proteins such as C reactive protein and inflammatory cytokines²⁵. IFN-γ has a critical role in recognizing and eliminating pathogens, but it has no direct effects on CD8⁺ T cells activation^26,27. Therefore, we focus on the IL-2 pathway to explore its possible effect on CD8⁺ T cells and lymphocytes.

This study is limited by sample size for critical patients with COVID-19 pneumonia, and clinical significance and power would be increased with more patients. However, our findings still provide evidences and clues for the diagnosis and treatment of critical patients with COVID-19 pneumonia. The progressive decrease of IL-2 in plasma may be a warning factor of disease deterioration in patients with COVID-19 pneumonia. For critical patients with COVID-19 pneumonia, appropriate IL-2 supplementation could be beneficial by improving the immune disorder so as to reduce mortality.