The recent increase in the pathogenesis of autoimmune diseases revealed the critical role of T cells. Investigation into immunometabolism has drawn attention to metabolic processes other than glycometabolism. In rapidly dividing immune cells, including T lymphocytes, the consumption of glutamine is similar to or higher than that of glucose even though glucose is abundant. In addition to contributing to many processes critical for cellular integrity and function, glutamine, as the most abundant amino acid, was recently regarded as an immunomodulatory nutrient. A better understanding of the biological regulation of glutaminolysis in T cells will provide a new perspective for the treatment of autoimmune diseases. In this review, we summarized the current knowledge of glutamine catabolism in CD4+ T-cell subsets of autoimmunity. We also focused on potential treatments targeting glutaminolysis in patients with autoimmune diseases. Knowledge of immunometabolism is constantly evolving, and glutamine metabolism may be a potential therapeutic target for autoimmune disease therapy.

https://www.frontiersin.org/articles/10.3389/fimmu.2022.986847/pdf

Glutaminolysis and CD4+ T-cell metabolism in autoimmunity: From pathogenesis to therapy prospects

T cells are critical players in adaptive immunity, driving the tissue injury and organ damage of patients with autoimmune diseases. Consequently, investigations on T cell activation, differentiation, and function are valuable in uncovering the disease pathogenesis, thus exploring promising therapeutics for autoimmune diseases. In recent decades, accumulating studies have pinpointed immunometabolism as the fundamental determinant in controlling T cell fate. Specifically, mitochondria, as a hub of intracellular metabolism, connect glucose, lipid, and amino acid metabolic pathways. Herein, we summarize metabolic adaptations of mitochondrial oxidative phosphorylation and the relevant glucose, lipid, and amino acid metabolism during T cell activation, differentiation, and function. Further, we focused on current updates of the molecular bases for metabolic reprogramming in autoimmune T cells and advances in exploring metabolic-targeted therapeutics against autoimmune diseases. This might facilitate the in-depth understanding of autoimmune pathogeneses and the clinical management of autoimmune diseases.

/pdf/mitochondrial-control-for-healthy-and-autoimmune-t-cells-150s5dck.pdf

Mitochondrial Control for Healthy and Autoimmune T Cells

T-cell dysfunction has been shown to play an important role in the pathogenesis of Sjögren’s syndrome (SS). In recent studies, the increased expression of BMP6 has been reported to be related to SS. However, the roles that BMP6 plays in immune homeostasis in the development of SS as well as the downstream signals activated by BMP6 remain unclear. In this study, we investigated the effects and molecular mechanisms of BMP6 on naive CD4+ T cells, showing that BMP6 could upregulate interferon (IFN)–γ secretion from CD4+ T cells through a ceramide/nuclear factor–κB pathway, with no effect on T-cell activation or proliferation. Moreover, an in vivo study showed that anticeramide treatment (myriocin) for an SS animal model (NOD/LtJ mice) could significantly decrease the IFN-γ expression and Th1 frequency in the salivary glands and suppress the inflammation infiltration in salivary glands and maintain the salivary flow rates, both of which reflect SS-like symptoms. This study identifies a promising target that could effectively attenuate the abnormal state of CD4+ T cells and reverse the progression of SS.

Anticeramide Improves Sjögren’s Syndrome by Blocking BMP6-Induced Th1

Augmented CD4+ T cell response in autoimmunity is characterized by extensive metabolic reprogramming. However, the epigenetic molecule that drives the metabolic adaptation of CD4+ T cells remains largely unknown. Here, we show that lysine acetyltransferase 6A (KAT6A), an epigenetic modulator that is clinically associated with autoimmunity, orchestrates the metabolic reprogramming of glucose in CD4+ T cells. KAT6A is required for the proliferation and differentiation of proinflammatory CD4+ T cell subsets in vitro, and mice with KAT6A-deficient CD4+ T cells are less susceptible to experimental autoimmune encephalomyelitis and colitis. Mechanistically, KAT6A orchestrates the abundance of histone acetylation at the chromatin where several glycolytic genes are located, thus affecting glucose metabolic reprogramming and subsequent CD4+ T cell responses. Treatment with KAT6A small-molecule inhibitors in mouse models shows high therapeutic value for targeting KAT6A in autoimmunity. Our study provides novel insights into the epigenetic programming of immunometabolism and suggests potential therapeutic targets for patients with autoimmunity. 

Lysine acetyltransferase 6A maintains CD4+ T cell response via epigenetic reprogramming of glucose metabolism in autoimmunity.

Introduction: Sjögren’s syndrome (SS) is a chronic autoimmune disorder characterized by exocrine gland dysfunction, leading to loss of salivary function. Histological analysis of salivary glands from SS patients reveals a high infiltration of immune cells, particularly activated CD4+ T cells. Thus, interventions targeting abnormal activation of CD4+ T cells may provide promising therapeutic strategies for SS. Here, we demonstrate that Hect, uba, and wwe domain containing 1 (HUWE1), a member of the eukaryotic Hect E3 ubiquitin ligase family, plays a critical role in CD4+ T-cell activation and SS pathophysiology. Methods: In the context of HUWE1 inhibition, we investigated the impact of the HUWE1 inhibitor BI8626 and sh-Huwe1 on CD4+ T cells in mice, focusing on the assessment of activation levels, proliferation capacity, and cholesterol abundance. Furthermore, we examined the therapeutic potential of BI8626 in NOD/ShiLtj mice and evaluated its efficacy as a treatment strategy. Results: Inhibition of HUWE1 reduces ABCA1 ubiquitination and promotes cholesterol efflux, decreasing intracellular cholesterol and reducing the expression of phosphorylated ZAP-70, CD25, and other activation markers, culminating in the suppressed proliferation of CD4+ T cells. Moreover, pharmacological inhibition of HUWE1 significantly reduces CD4+ T-cell infiltration in the submandibular glands and improves salivary flow rate in NOD/ShiLtj mice. Conclusion: These findings suggest that HUWE1 may regulate CD4+ T-cell activation and SS development by modulating ABCA1-mediated cholesterol efflux and presents a promising target for SS treatment.

/pdf/hect-uba-and-wwe-domain-containing-1-represses-cholesterol-3f3lowob.pdf

HECT, UBA and WWE domain containing 1 represses cholesterol efflux during CD4+ T cell activation in Sjögren’s syndrome

Previous studies have shown that abnormal metabolic reprogramming in CD4+ T cells could explain the occurrence of several autoimmune disorders, including Sjogren's syndrome (SS). However, therapeutic targets of the abnormal metabolism of CD4+ T cells remain to be explored. Here, we report that glutaminase 1 (Gls1), a pivotal factor in glutaminolysis, might be involved in the pathogenesis of SS. The expression of Gls1 was upregulated in infiltrated labial CD4+ T cells and circulating CD4+ T cells of SS patients. Inhibiting Gls1 with BPTES significantly abolished the proliferation rate, as indicated by EdU, CFSE, and Western blot analyses. Additionally, BPTES downregulated the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) values of activated CD4+ T cells from SS mice. In vivo, we injected different doses of BPTES into SS-like NOD/Ltj mice and found that 10 mg/kg BPTES significantly restored the salivary flow rate. Histological and qRT–PCR analyses showed that this concentration of BPTES attenuated lymphocytic infiltration and the numbers of PCNA-positive cells and CD4+ T cells. The proportions of IFNγ-producing cells and IL-17A-producing cells and the expression of several proinflammatory cytokines, including IFNγ and IL-17A, were also affected in the salivary glands of SS-like mice. Cytokine production in circulating serum was analyzed and showed that BPTES downregulated the effector functions of Th17 cells and Th1 cells. Collectively, these results indicate a positive relationship between Gls1 and SS development. Pharmacological inhibition of Gls1 with BPTES could normalize the effector functions of CD4+ T cells and effectively attenuate the symptoms of SS.

/pdf/pharmacological-inhibition-of-glutaminase-1-normalized-the-1o0yn3gz.pdf

Pharmacological Inhibition of Glutaminase 1 Normalized the Metabolic State and CD4+ T Cell Response in Sjogren's Syndrome

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Lysine acetyltransferase 6A maintains CD4+ T cell response via epigenetic reprogramming of glucose metabolism in autoimmunity.

Pharmacological Inhibition of Glutaminase 1 Normalized the Metabolic State and CD4+ T Cell Response in Sjogren's Syndrome