Dietary Intervention Impacts Immune Cell Functions and Dynamics by Inducing Metabolic Rewiring

Abstract

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.

Keywords: AMPK; GCN2; calorie restriction; dietary intervention; fasting; mTOR; metabolic rewiring.

Figure 1

Overview of the nutritional signals regulating immune responses. Calorie restriction (CR) and fasting lowers plasma IGF-1 levels and downregulates PI3K/Akt/mTOR signaling pathways. At a low-energy status, two major energy sensors: adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT) family proteins, are activated by AMP and NAD⁺, respectively. GCN2 acts as a sensor of amino acid deficiency to regulate the differentiation and polarization of T cells and macrophages. β-HB also contributes to the anti-inflammatory effects by suppressing NLRP3 inflammasome activation. The white and orange boxes represent signal messengers and enzymes/transcription factors, respectively. The pathways depicted by black arrows and red bars represent the activation and inhibition by dietary restriction, respectively.

Figure 2

The immunomodulating effects of mTORC1, ACC1, and FoxO1/3. Fasting or calorie restriction (CR) suppresses mTORC1 and ACC1 activation and activates FoxO1/3 pathways. (A) mTORC1 inhibition enhances ketogenesis and reduces glycolysis and glutaminolysis. mTORC1 inhibition also induces autophagy in macrophage and suppresses Th1, Th17, and M1 macrophage differentiation. (B) ACC1 inhibition reduces FAS, which facilitates development of CD4⁺ memory T cells and Treg cells and conversely suppresses Teff (Th1, Th2, and Th17) responses. (C) Activation of FoxO1 and/or FoxO3 induces apoptosis and inactivates NF-κB. FoxO1 or FoxO3 also regulates phenotypes of macrophages, suppresses Th17 response, and induces development of CD8⁺ memory T cells and Treg cells.

Figure 3

Bone marrow serves as a reservoir for several immune cell subsets in response to calorie restriction (CR) or fasting. Under low-energy conditions, naïve B cells, monocytes, and memory CD8⁺ T cells accumulate in the bone marrow. Fasting lowers CXCL13 levels in PPs and reciprocally increases the expression in the bone marrow. This leads to the migration of naïve B cells from PPs to the bone marrow. On the other hand, GC B cells and IgA⁺ B cells undergo apoptosis. Fasting diminishes circulating CCL2 levels through AMPK/PPARα signaling activation. Consequently, the egress of monocytes from the bone marrow is suppressed. Dietary restriction drives CD8⁺ memory T cells to traffic toward the bone marrow in the S1P/S1PR1- and CXCL12/CXCR4-dependent manner. The bone marrow microenvironment provides a tissue-specific niche for the maintenance of memory CD8⁺ T cells with low glucocorticoid concentration and abundant adipocytes.