Today's article deals with a recently published Brazilian scientific study on an enzyme that can cause T-helper cells to go awry.1
T-helper lymphocytes are critically involved in the pathogenesis of autoimmune diseases. Depending on which antigen and under which conditions naive helper T-cells come into contact with an antigen, differentiation into various subtypes is possible. These sub-types include Th1, Th2, Th17 and regulatory T cells (Tregs). A further subdivision takes place in Th17 and Th17.1 cells. The latter are involved in the development of a whole range of autoimmune diseases. In sarcoidosis, multiple sclerosis and chronic inflammatory diseases, the Th17.1 cells and their pro-inflammatory cytokines play a key role. Gaining a better understanding of this dysregulated immune response is an essential building block for targeted personalised medicine.
The differentiation and pathogenicity of Th17 cells depends on a very specific metabolic reprogramming that causes a shift towards glycolysis. The pyruvate kinase M2 is found within the human organism in the foetal stage and in tumour tissue. The enzyme therefore serves as a non-specific tumour marker and, from a functional point of view, is involved in glycolysis. A research group from Brazil was able to show that pyruvate kinase M2, in addition to its role in tumour proliferation, is also extremely relevant for the differentiation of Th17 cells and autoimmune processes.1
We know that Th17 cells have an important function within the adaptive immune response and that dysregulation of these cells can result in autoimmune diseases. Interleukin-6 and TGF-beta jointly induce the differentiation of Th17 cells. According to recent study results, immune cells undergo a dynamic metabolic reprogramming process to maintain the bioenergetic and biosynthetic basis for subsequent activation, proliferation and differentiation.
The mTORC1 (mammalian target of rapamycin complex 1) and the HIF1-alpha (hypoxia-inducible factor 1α) play a central role in this process. The metabolic reprogramming of immune cells towards aerobic glycolysis (in tumour cells this phenomenon is known as the Warburg effect) is of great importance for the differentiation of Th17 cells. 2-Deoxy-d-glucose leads to a blockage of glycolysis and is associated in vitro with an inhibition of the Th17 cells.1
The dimeric pyruvate kinase has the ability to translocate into the nucleus where it acts as a transcriptional coactivator to regulate gene expression. In doing so, it interacts with the HIF1-alpha, among others. The drug inhibition of the translocation of pyruvate kinase M2 into the nucleus is accompanied by reduced aerobic glycolysis and reduced proliferation of tumour cells.1
In their experimental study, the research group observed that pyruvate kinase M2 can influence the differentiation of Th17 cells by activating STAT3, but not Th1, Th2 or Treg cells. A T-cell-specific deletion of pyruvate kinase M2 was associated with impaired development of Th17 cells. The reduction of the Th17 immune response in the mouse model led to a decrease in demyelinating processes in autoimmune encephalomyelitis.1
Reference:
1. Damasceno L. E. A. et al. (2020). PKM2 promotes Th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation. J Exp Med. 2020 Oct 5;217(10):e20190613.