Accumulating evidence has shown that nutrient metabolism is closely associated with the differentiation and functions of various immune cells. Cellular metabolism, including aerobic glycolysis, fatty acid oxidation, and oxidative phosphorylation, plays a key role in germinal center (GC) reaction, B-cell trafficking, and T-cell-fate decision. Furthermore, a quiescent metabolic status consolidates T-cell-dependent immunological memory. Therefore, dietary interventions such as calorie restriction, time-restricted feeding, and fasting potentially manipulate immune cell functions. For instance, intermittent fasting prevents the development of experimental autoimmune encephalomyelitis. Meanwhile, the fasting response diminishes the lymphocyte pool in gut-associated lymphoid tissue to minimize energy expenditure, leading to the attenuation of Immunoglobulin A (IgA) response. The nutritional status also influences the dynamics of several immune cell subsets. Here, we describe the current understanding of the significance of immunometabolism in the differentiation and functionality of lymphocytes and macrophages. The underlying molecular mechanisms also are discussed. These experimental observations could offer new therapeutic strategies for immunological disorders like autoimmunity.

The bone serves as a reservoir for several immune cell subsets in response to the low-energy status such as fasting. We previously demonstrated that naïve B cells transiently migrate from Peyer’s patches to the bone marrow during fasting in mice. This B-cell dynamics is attributed to upregulation of CXCL13 in the bone during fasting. However, CXCL13 producers in the bone remain to be determined. We observed that lineage-negative population from the bone is responsible for Cxcl13 expression. To further clarify the CXCL13 producers, we performed single-cell RNA-sequencing of bone linage-negative cells from Ad libitum-fed mice and fasting mice. UMAP analysis manifested that the numbers of fibroblasts and multipotent stem cells (MSCs) were increased in the fasting group. Interestingly, Cxcl13-producing cells were identified as osteogenic-MSCs characterized by expressions of Sca-1 (immature cells marker), Sema3c, and Dcn (osteogenic cells maker). This population also expressed an inflammatory cytokine Il6. Meanwhile, mature osteoblasts and chondrocytes expressed neither Cxcl13 nor Il6. Furthermore, co-culture with the plasma from fasting mice upregulated CXCL13 expression in osteogenic-MSCs in vitro, suggesting that a soluble factor(s) in the circulation induces CXCL13. Taken together, osteogenic-MSCs in the bone may sense nutritional status and produce CXCL13 to regulate naïve B-cell dynamics along the gut-bone axis. The pathophysiological role of CXCL13-producing osteogenic-MSCs is currently under investigation. none