Vitamin D can reduce severity in COVID-19 through regulation of PD-L1

Abstract

COVID-19 is a highly contagious viral infection that has killed millions of people around the world. The most important diagnostic feature of COVID-19 is lymphocyte depletion, particularly the depletion of T cells. In COVID-19 infections, there is a link between destruction of T cells and increased expression of inhibitory immune checkpoint molecules (PD-1/PD-L1) on T cell surfaces. It was shown that PD-1/PD-L1 levels increase in severely COVID-19 infected individuals. Higher proinflammatory cytokine levels cause increased PD-1/PD-L1 expression. In severe COVID-19, higher proinflammatory cytokine levels may increase PD-1/PD-L1. Vitamin-D is an important immune regulator. It is known that the numbers of CD4 + and CD8 + T lymphocytes decrease in vitamin D deficiency while vitamin D supplementation increases CD + 4 lymphocytes. Vitamin D can increase regulatory T cell (Treg) activity. Vitamin D also has a diminishing effect on proinflammatory cytokines. In severe COVID-19 cases, vitamin D supplementation may inhibit the increase of PD-L1 expression through reducing proinflammatory cytokine levels. Thus, vitamin D supplementation could eliminate the suppressive effect of PD-L1 on CD4 + and CD8 + T cells, preventing lymphopenia and reducing disease severity and mortality in patients infected with COVID-19. Besides, vitamin D supplementation can reduce inflammation by increasing Treg activity. The aim of this letter is to discuss the functions of inhibitory immune checkpoint molecules and their effects on dysfunction and depletion of T-cells as well as to explain the possible modulatory effect of vitamin D on these checkpoints and T cells.

Vitamin D Status Is Associated With Immune Checkpoint Inhibitor Efficacy and Immune-related Adverse Event Severity in Lung Cancer Patients: A Prospective Cohort Study

“…1,25(OH)D 2 induces cell surface expression of PD-L1 in epithelial and myeloid cells, 9 and VitD supplementation reduces the suppressive effect of PD-L1 on CD4 + and CD8 + T cells. 5,28 Thus, VitD might increase the proportion of tumor cells targetable by anti-PD-1 or anti-PD-L1 agents, thereby enhancing ICI responses. 11,12 Also, in a study of ICI-treated patients, baseline 25(OH)D levels were associated with nivolumab concentrations in NSCLC patients and nivolumab concentrations were affected by single nucleotide polymorphisms in VitD pathway-related genes.…”

“…PD-L1, often expressed on tumor cells, is the cell surface glycoprotein that interacts with PD-1. 1,25(OH)D 2 induces cell surface expression of PD-L1 in epithelial and myeloid cells,9 and VitD supplementation reduces the suppressive effect of PD-L1 on CD4 + and CD8 + T cells 5,28. Thus, VitD might increase the proportion of tumor cells targetable by anti-PD-1 or anti-PD-L1 agents, thereby enhancing ICI responses 11,12.…”

Vitamin D and estrogen steroid hormones and their immunogenetic roles in Infectious respiratory (TB and COVID-19) diseases

“…PD-1, when expressed, is a potent immune regulator because it indicates an activation threshold before an immune response is initiated, thus limiting the activity of T and B cells preventing the proliferation and differentiation of T cells ( Schönrich and Raftery, 2019 ; Aygun, 2022 ).…”

“…Interestingly, PD-1/PD-L1, is regulated through several signalling pathways activated by pro-inflammatory cytokines ( Aygun, 2022 ). As already reported, VD 3 has a potential role to reduce inflammation and a recent study reported that this hormone can regulate PD-1/PD-L1 axis by increasing PD-L1 when they are too low or decreasing PD-L1 when are too high, i.e., through T-cell production.…”

Recent Insight on Regulations of FBXW7 and Its Role in Immunotherapy

“…Therefore, it is possible that FBW7 is capable of interfering with the viral RNA synthesis in the early stage of SARS-CoV-2 invasion via stabling RIG-I. Moreover, the expression of PD-1and PD-L1 was reported to increase in patients with severe COVID-19 (183). The abundance of PD-1 demonstrates a closed correlation with the severity of the disease (184).…”