The growth, survival, and performance of immune effector functions of immune cells are closely linked to metabolism, and immune cells with different functions rely on various metabolic pathways to achieve their immune functions [1]. T cells metabolize resources, including glucose, glutamine, and fatty acids, to create adenosine triphosphate (ATP), which helps them satisfy their energy needs. Metabolic reprogramming is particularly important in T cell biology, and two main processes supply ATP intracellularly, glycolysis and oxidative phosphorylation (OXPHOS). Glycolysis is the pathway that breaks down glucose into pyruvate, and many rapidly dividing cells use OXPHOS to produce lactate under aerobic conditions, which is known as the Warburg effect or aerobic glycolysis [2]. The primary metabolic process needed to activate T cells is glycolysis, naive T cells abruptly transition from OXPHOS to glycolysis when they come into contact with the T cell receptor. Effector T cells are highly utilized for proliferation [3] and maintenance of effector functions by glycolysis, whereas memory T cells rely on fatty acid oxidation of mitochondria for development and long-term survival [1,2,4].

Follicular helper T (Tfh) cells, a subset of CD4+ helper T (Th) cells, provide essential help for B cell affinity maturation, class switch recombination, and plasma and memory B cell generation within the germinal center (GC) [[5], [6], [7], [8]]. The master regulator of Tfh cells, B cell lymphoma 6 (BCL6), is required to regulate Tfh cell development and GC responses [9,10]. Tfh cells primarily produce the B helper cytokine interleukin (IL)-21 and express a set of featured markers, such as chemokine receptor 5 (CXCR5), inducible T cell costimulator, and programmed cell death 1 (PD-1) [11]. Different Th cells use various metabolic pathways depending on their function. Tfh cells exhibit increased glycolysis [12]. However, the importance of glycolysis in Tfh cell differentiation is not clear [13]. Metabolic abnormalities associated with abnormal T cell function are present in some autoimmune diseases, such as systemic lupus erythematosus (SLE) [13], a long-term autoimmune disease that involves multiple organ systems. Glycolysis rates are increased in chronically active T cells from both patients with SLE and mice with lupus [14,15], which results in increased mechanistic target of rapamycin complex 1 (mTORC1) signaling and promotes autoimmunity, including the production of autoantibodies and deposition of immune complexes in the glomeruli [16]. Expansion of Tfh cells is closely associated with SLE [17,18] and increased circulating Tfh cells in the blood of patients with SLE correlates with disease severity [19,20]. However, not much research has connected the pathophysiology of SLE with glycolysis of Tfh cells.

The glycolysis enzyme pyruvate kinase (PK) converts phosphoenolpyruvate (PEP) into pyruvate by acting on it. Pyruvate kinase isozyme 2 (PKM2), an isoform of PK, is mainly expressed in proliferating tissues and acts as a key regulator of tumor metabolism [21,22]. PKM2 tetramers and dimers are composed of the same monomer. The tetramer routes pyruvate from glucose metabolism to the tricarboxylic acid cycle during glucose metabolism, while the PKM2 dimer results in glucose utilization in the pentose phosphate, uric acid, and polyol pathways [22,23]. PKM2 can be induced to translocate from the cytoplasm to the nucleus. According to its C-terminal nuclear localization signal, PKM2 then forms dimers in the nucleus. The dimeric PKM2 in the nucleus is associated with the protein kinase activity of various transcription factors and affects various signaling pathways [22,24,25]. TEPP-46 is a well-characterized allosteric activator of PKM2 that causes tetramerization, blocks translocation into the nucleus, and increases the canonical enzymatic activity of PKM2 [22,26]. Recently, TEPP-46 was shown to inhibit the basic signaling pathway of CD4+ T cells, thereby decreasing glycolysis and reducing their activation, proliferation, and cytokine production [27]. Previous studies have indicated that PKM2, a key enzyme in glycolysis, is expressed at increased levels during CD4+ T cell activation and regulates Th1 and Th17 cell differentiation [27,28]. Here, we speculate that modulating Tfh cell differentiation by controlling PKM2 may lessen the etiology of SLE.