Abstract
Ampk is an energy gatekeeper that responds to decreases in ATP by inhibiting energy-consuming anabolic processes and promoting energy-generating catabolic processes. Recently, we showed that Lkb1, an understudied kinase in B lymphocytes and a major upstream kinase for Ampk, had critical and unexpected roles in activating naïve B cells and in germinal center formation. Therefore, we examined whether Lkb1 activities during B cell activation depend on Ampk and report surprising Ampk activation with in vitro B cell stimulation in the absence of energy stress, coupled to rapid biomass accumulation. Despite Ampk activation and a controlling role for Lkb1 in B cell activation, Ampk knockout did not significantly affect B cell activation, differentiation, nutrient dynamics, gene expression, or humoral immune responses. Instead, Ampk loss specifically repressed the transcriptional expression of IgD and its regulator, Zfp318. Results also reveal that early activation of Ampk by phenformin treatment impairs germinal center formation but does not significantly alter antibody responses. Combined, the data show an unexpectedly specific role for Ampk in the regulation of IgD expression during B cell activation.
Highlights
B lymphocyte activation is an early step in a humoral immune response, whereby a naïve B cell with a unique antigen receptor recognizes its cognate antigen to trigger growth, division, and differentiation
We investigated whether Ampk, a major downstream target of Lkb[1], was required for B cell activation[4,5]
We examined the phosphorylation of Ampk at T172, a marker residue for Ampk activation[22] and determined that Ampk activation occurs between 18–24 hours post-stimulation of B cells with anti-CD40 antibody plus interleukin (IL)-4 that persists at least through 72 hours (Fig. 1A)
Summary
B lymphocyte activation is an early step in a humoral immune response, whereby a naïve B cell with a unique antigen receptor recognizes its cognate antigen to trigger growth, division, and differentiation. Ampk is an energy sensor that couples metabolism with nutrient availability during periods of energetic stress, as might occur during rapid B cell expansion and differentiation[8]. Ampk does this by sensing increasing levels of ADP or AMP with reducing levels of ATP in a cell, which triggers the phosphorylation of well characterized substrate proteins including Tsc[2], Acc1/2, and Tbc1d1 to inhibit protein synthesis, promote fatty acid oxidation, upregulate glycolysis, and restore overall cell. Given the unexpected role for Lkb[1] loss in B cells in triggering a GC reaction, we sought to determine role(s) for Ampk during B cell activation
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