Functionally significant metabolic differences between B and T lymphocyte lineages

Abstract

Summary Activation of B and T lymphocytes leads to major remodelling of the metabolic landscape of the cells enabling their post‐activation functions. However, naive B and T lymphocytes also show metabolic differences, and the genesis, nature and functional significance of these differences are not yet well understood. Here we show that resting B‐cells appeared to have lower energy demands than resting T‐cells as they consumed lower levels of glucose and fatty acids and produced less ATP. Resting B‐cells are more dependent on OXPHOS, while T‐cells show more dependence on aerobic glycolysis. However, despite an apparently higher energy demand, T lineage cells showed lower rates of protein synthesis than equivalent B lineage stages. These metabolic differences between the two lineages were established early during lineage differentiation, and were functionally significant. Higher levels of protein synthesis in B‐cells were associated with increased synthesis of MHC class II molecules and other proteins associated with antigen internalization, transport and presentation. The combination of higher energy demand and lower protein synthesis in T‐cells was consistent with their higher ATP‐dependent motility. Our data provide an integrated perspective of the metabolic differences and their functional implications between the B and T lymphocyte lineages.

The Unfolded Protein Response in Immune Cells as an Emerging Regulator of Neuroinflammation

“…IRE1 via XBP1s controls eosinophil, DC, and plasma cell development (Reimold et al, 2001;Iwakoshi et al, 2007;, which contribute to neuroinflammation in MS and Experimental Autoimmune Encephalomyelitis (EAE), the mouse model of MS (Greter et al, 2005;Wensky et al, 2005;Mundt et al, 2019;Pröbstel et al, 2020). Furthermore, DCs and plasma cells show constitutive UPR activation and display an elevated protein synthesis rate in steady state (Osorio et al, 2014;Khalsa et al, 2019;Mendes et al, 2020). In these cell types, XBP1s maintains ER architecture, whereas RIDD controls functional aspects, including antigen cross-presentation and cDC1s survival, or immunoglobulin production by plasma cells (Benhamron et al, 2014;Osorio et al, 2014;Tavernier et al, 2017).…”

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“…However, data on B cell lymphocyte metabolism is relatively scarce, as the previously mentioned studies primarily concentrated on T lymphocytes. Recent evidence showed that resting B cells seem to have lower energy requirements than resting T cells as they consumed less glucose and fatty acids and, consequently, produced less ATP [ 63 ]. Nevertheless, resting B cells primarily rely on OXPHOS to meet their metabolic demands and have a higher mitochondrial mass [ 63 ].…”

“…Recent evidence showed that resting B cells seem to have lower energy requirements than resting T cells as they consumed less glucose and fatty acids and, consequently, produced less ATP [ 63 ]. Nevertheless, resting B cells primarily rely on OXPHOS to meet their metabolic demands and have a higher mitochondrial mass [ 63 ]. Despite these differences in the resting state, B cells share some metabolic characteristics with T cells upon activation.…”

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“…Increased plasma glucose usage may restrict this nutrient from Tfh cells; however, Tfh cells downregulate glycolysis in response to expression of their lineage defining transcription factor B cell lymphoma 6 ( Bcl6 ). The change in metabolic preference is concurrent with a change in activation state and is functionally specific to immune cell types ( Khalsa et al, 2019 ). Feedback mechanisms through cytokine signaling, such as anti-inflammatory interleukin-10 ( IL -10), eventually contribute to reduced activation states to prevent continuous activation and cellular exhaustion ( Couper et al, 2008 ; Saraiva and O’Garra, 2010 ; Khalsa et al, 2019 ).…”