Peripheral T cell lymphopenia in COVID-19: potential mechanisms and impact

Abstract

Immunopathogenesis involving T lymphocytes, which play a key role in defence against viral infection, could contribute to the spectrum of COVID-19 disease and provide an avenue for treatment. To address this question, a review of clinical observational studies and autopsy data in English and Chinese languages was conducted with a search of registered clinical trials. Peripheral lymphopenia affecting CD4 and CD8 T cells was a striking feature of severe COVID-19 compared with non-severe disease. Autopsy data demonstrated infiltration of T cells into organs, particularly the lung. Seventy-four clinical trials are on-going that could target T cell-related pathogenesis, particularly IL-6 pathways. SARS-CoV-2 infection interrupts T cell circulation in patients with severe COVID-19. This could be due to redistribution of T cells into infected organs, activation induced exhaustion, apoptosis, or pyroptosis. Measuring T cell dynamics during COVID-19 will inform clinical risk-stratification of hospitalised patients and could identify those who would benefit most from treatments that target T cells.

Keywords: CD4 cell; CD8 cell; COVID-19; SARS-CoV-2 virus; T cell biology.

In this review, we demonstrate that CD4⁺ and CD8⁺ T cell lymphopenia is a feature of severe COVID-19 compared with moderate disease in hospitalised patients. Pathology data indicate T cell infiltration into infected organs, particularly the lung. Potential mechanisms affecting T cells in severe disease due to SARS-CoV-2 infection include T cell redistribution and sequestration, pyroptosis, and apoptosis.

Figure 1.

Flow chart of the study selection process.

Figure 2.

Forest plot of T cell subsets in patients with severe and non-severe COVID-19. CD3⁺, CD4⁺ and CD8⁺ T cell counts are significantly lower in patients with severe COVID-19 compared with those in patients with non-severe COVID-19 (P < 0.00001). The effect of severity of disease on the CD4:CD8 ratio was inconclusive (P = 0.08). Black diamond represents test for overall effect of 40 studies.

Figure 3.

Hypothesis for peripheral T cell lymphopenia during SARS-CoV-2 infection and severe disease. According to experimental data from peripheral blood of patients with severe COVID-19, we propose two drivers for peripheral lymphopenia. Firstly, T lymphocytes in the periphery are attracted by chemokines released by infected cells and immune cells at the site of disease and migrate out of the periphery to infected organs, mainly the lungs. Secondly, functionally exhausted T lymphocytes and activation of Th1/Th2/Th17 responses at the site of disease, fail to achieve viral containment, and undergo cell death through a variety of mechanisms including apoptosis and pyroptosis. It is likely that interruption of the normal circulation of T cells is the key component in this cycle.