Figure 2. Spike protein induction of an inflammatory response. The events leading to hyper-activation of inflammation can concurrently occur through (a) a CD4+ T cell over-production via the stimulation of NIK (the alternative NF-κB pathway) and thereby loss of self-antigen tolerance, and (b) a promotion of inflammation through the inhibition of IRF3 and type I IFN, and subsequent impairment of mTOR activity. [111,116,153,158,159,161,162].
11. TGF-β Signalling and the Development of a Th17 Response
In the remarkable work of Liu L et al. [33], the responses of immune cells to the inactivated SARS-CoV-2 vaccine, as shown in Table 1, cause enhanced TGF-β signalling. This is in addition to the increased NF-kB response. This is enhanced only in some subtypes of immune cells. Specifically, the CD4+ Treg cells, CD4+ T proliferative cells, monocytes and dendritic cells show intense TGF-β signalling. These immune cells have roles that impact the efficient control and development of Treg responses [3]. Furthermore, intense TGF-β signalling and increased IL-6 and TNF-α expression are observed when the immune cells encounter huge amounts of the SARS-CoV-2 mRNA coded spike protein in vaccinated individuals [163].
As shown in Table 1, the T cell subsets (including the Treg cells) that show intense TGF-β signalling are also resistant to hypoxia effects. For the Τ cells to sustain themselves in this environment, they likely express adequate hypoxia inducible factors (HIFs). Moreover, HIF has been shown to be protective against uptake of the spike protein through multiple mechanisms [164].
Table 1. The hypoxia effect, and TGF-β signalling responses of progenitor lineages of immune cell subsets to the inactivated SARS-CoV-2 vaccine containing the spike protein mRNA. Adapted from Liu et al., 2021 [33].