Mitochondrial function provides instructive signals for activation-induced B-cell fates

Abstract

During immune reactions, functionally distinct B-cell subsets are generated by stochastic processes, including class-switch recombination (CSR) and plasma cell differentiation (PCD). In this study, we show a strong association between individual B-cell fates and mitochondrial functions. CSR occurs specifically in activated B cells with increased mitochondrial mass and membrane potential, which augment mitochondrial reactive oxygen species (mROS), whereas PCD occurs in cells with decreased mitochondrial mass and potential. These events are consequences of initial slight changes in mROS in mitochondriahigh B-cell populations. In CSR-committed cells, mROS attenuates haeme synthesis by inhibiting ferrous ion addition to protoporphyrin IX, thereby maintaining Bach2 function. Reduced mROS then promotes PCD by increasing haeme synthesis. In PCD-committed cells, Blimp1 reduces mitochondrial mass, thereby reducing mROS levels. Identifying mROS as a haeme synthesis regulator increases the understanding of mechanisms regulating haeme homeostasis and cell fate determination after B-cell activation.

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

“…In fact, compared with less dividing cells, highly proliferating CD8 + T cells in response to tumor antigens contained more cellular ROS, larger mitochondrial mass, higher mitochondrial membrane potential, and more mitochondrial superoxide, a major source of mitochondrial ROS (25), clearly indicating activation of mitochondria in TR CTLs in vivo by PD-1 blockade (Fig. 2D).…”

Germinal Center B Cell Dynamics

“…Understanding what signals induce activation of RelA in vivo may provide valuable clues to the cellular processes involved in PC differentiation. Other recent developments have included the notions that epigenetic modifiers such as EZH2 and MOZ may influence the balance between PC and Bmem differentiation (Beguelin et al, 2013; Caganova et al, 2013; Good-Jacobson et al, 2014) and that mitochondrial function may provide instructive signals that can skew activation-induced B-cell fates (Jang et al, 2015). …”

Mitochondrial Pyruvate Import Promotes Long-Term Survival of Antibody-Secreting Plasma Cells

“…Glucose uptake is used to fuel glycolysis, electron transport chain activity, and synthesis of lipids for expansion of the endoplasmic reticulum (Dufort et al, 2014; Garcia-Manteiga et al, 2011). X-box binding protein 1 drives expression of mitochondrial and endoplasmic reticulum biosynthesis and stress-related genes (Jang et al, 2015; Shaffer et al, 2004; van Anken et al, 2003). By providing metabolic substrates, autophagy is also important for plasma cells (Pengo et al, 2013).…”