Dynamic mitochondrial transcription and translation in B cells control germinal centre entry and lymphomagenesis

Abstract

Germinal centre (GC) B cells undergo proliferation at very high rates in a hypoxic microenvironment, but the cellular processes driving this are incompletely understood. Here we show that the mitochondria of GC B cells are highly dynamic, with significantly upregulated transcription and translation rates associated with the activity of transcription factor mitochondrial A (Tfam). Tfam, whilst also necessary for normal B cell development, is required for entry of activated GC-precursor B cells into the germinal centre reaction, and deletion of Tfam significantly impairs GC formation, function, and output. Loss of Tfam in B cells compromises the actin cytoskeleton and impairs cellular motility of GC B cells in response to chemokine signalling, leading to their spatial disorganisation. We show that B cell lymphoma substantially increases mitochondrial translation, and deletion of Tfam in B cells is protective against the development of lymphoma in a c-Myc transgenic model. Finally, we show that pharmacologic inhibition of mitochondrial transcription inhibits growth of GC-derived human lymphoma cells, and induces similar defects in the actin cytoskeleton.

The aged microenvironment impairs BCL6 and CD40L induction in CD4+ T follicular helper cell differentiation

“…Young (2‐3‐month‐old) and aged (18‐22‐month‐old) mice were immunized via intraperitoneal injection with nitro‐phenyl hapten conjugated to ovalbumin (NP‐OVA) emulsified in alum adjuvant. Analysis of GC B cells, gated within B220 + CD19 + lymphocytes (Rodig et al., 2005; Wang & Carter, 2005; Yazicioglu et al., 2023), revealed diminished expansion of NP‐specific GL7 + Fas + GC B cells in aged mice at 14 days postimmunization (dpi) as compared to young mice (Figure S1A, Figure 1a,b), which corresponded to reduced recovery of NP‐specific IgG1 from aged mouse serum (Figure 1c). We administered a standard antigen dose to all mice, as others have done when administering NP‐OVA to either aged (Almanan et al., 2020; Lefebvre et al., 2012; Silva‐Cayetano et al., 2023) or obese mice (Deng et al., 2021).…”

Serine synthesis controls mitochondrial biogenesis in macrophages

“…Here, we have revealed a mechanism involved in mitochondrial biogenesis. Mitochondria serve as an important organelle that determines the fate and function of immune cells (e.g., B cells, T cells, and macrophages) (33,(38)(39)(40). PHGDH is not only presented in the cytoplasm but also located within mitochondria, which may play an indispensable role in mitochondrial functions across various cell types (38,41).…”

“…Mitochondria serve as an important organelle that determines the fate and function of immune cells (e.g., B cells, T cells, and macrophages) (33,(38)(39)(40). PHGDH is not only presented in the cytoplasm but also located within mitochondria, which may play an indispensable role in mitochondrial functions across various cell types (38,41). Although PHGDH deficiency has been shown to increase the mitochondrial number in endothelial cells (18), welldesigned investigation is required to elucidate the specific role of PHGDH in the mitochondrial function of immune cells.…”

Plasma cell differentiation, antibody quality, and initial germinal center B cell population depend on glucose influx rate

“…B cells that were GL7 neg -a population that has been treated as "activated precursors" or pre-GC blasts (38). This result shows that proliferation amongst some B cells in vivo is reduced by inactivation of Slc2a1 at the outset.…”