bims-nastce 2021-08-01 papers

World J Gastroenterol. 2021 Jul 07. 27(25): 3705-3733

Incorporating mucosal-associated invariant T cells into the pathogenesis of chronic liver disease.

Mucosal-associated invariant T (MAIT) cells have been described in liver and non-liver diseases, and they have been ascribed antimicrobial, immune regulatory, protective, and pathogenic roles. The goals of this review are to describe their biological properties, indicate their involvement in chronic liver disease, and encourage investigations that clarify their actions and therapeutic implications. English abstracts were identified in PubMed by multiple search terms, and bibliographies were developed. MAIT cells are activated by restricted non-peptides of limited diversity and by multiple inflammatory cytokines. Diverse pro-inflammatory, anti-inflammatory, and immune regulatory cytokines are released; infected cells are eliminated; and memory cells emerge. Circulating MAIT cells are hyper-activated, immune exhausted, dysfunctional, and depleted in chronic liver disease. This phenotype lacks disease-specificity, and it does not predict the biological effects. MAIT cells have presumed protective actions in chronic viral hepatitis, alcoholic hepatitis, non-alcoholic fatty liver disease, primary sclerosing cholangitis, and decompensated cirrhosis. They have pathogenic and pro-fibrotic actions in autoimmune hepatitis and mixed actions in primary biliary cholangitis. Local factors in the hepatic microenvironment (cytokines, bile acids, gut-derived bacterial antigens, and metabolic by-products) may modulate their response in individual diseases. Investigational manipulations of function are warranted to establish an association with disease severity and outcome. In conclusion, MAIT cells constitute a disease-nonspecific, immune response to chronic liver inflammation and infection. Their pathological role has been deduced from their deficiencies during active liver disease, and future investigations must clarify this role, link it to outcome, and explore therapeutic interventions.

Keywords: Antimicrobial; Immune regulatory; Innate-like lymphocytes; Mucosal-associated invariant T cell; Pathogenic

DOI: https://doi.org/10.3748/wjg.v27.i25.3705

Front Immunol. 2021 ;12 678355

The Alterations in and the Role of the Th17/Treg Balance in Metabolic Diseases.

Siwen Zhang, Xiaokun Gang, Shuo Yang, Mengzhao Cui, Lin Sun, Zhuo Li, Guixia Wang.

Chronic inflammation plays an important role in the development of metabolic diseases. These include obesity, type 2 diabetes mellitus, and metabolic dysfunction-associated fatty liver disease. The proinflammatory environment maintained by the innate immunity, including macrophages and related cytokines, can be influenced by adaptive immunity. The function of T helper 17 (Th17) and regulatory T (Treg) cells in this process has attracted attention. The Th17/Treg balance is regulated by inflammatory cytokines and various metabolic factors, including those associated with cellular energy metabolism. The possible underlying mechanisms include metabolism-related signaling pathways and epigenetic regulation. Several studies conducted on human and animal models have shown marked differences in and the important roles of Th17/Treg in chronic inflammation associated with obesity and metabolic diseases. Moreover, Th17/Treg seems to be a bridge linking the gut microbiota to host metabolic disorders. In this review, we have provided an overview of the alterations in and the functions of the Th17/Treg balance in metabolic diseases and its role in regulating immune response-related glucose and lipid metabolism.

Keywords: MAFLD; T2DM; Th17; Treg; chronic inflammation; metabolic disease; obesity

DOI: https://doi.org/10.3389/fimmu.2021.678355

Pediatr Gastroenterol Hepatol Nutr. 2021 Jul;24(4): 377-383

Effector Memory CD8+ and CD4+ T Cell Immunity Associated with Metabolic Syndrome in Obese Children.

Da-Hee Yang, Hyunju Lee, Naeun Lee, Min Sun Shin, Insoo Kang, Ki-Soo Kang.

Purpose: We investigated the association of effector memory (EM) CD8+ T cell and CD4+ T cell immunity with metabolic syndrome (MS).
Methods: Surface and intracellular staining of peripheral blood mononuclear cells was performed. Anti-interleukin-7 receptor-alpha (IL-7Rα) and CX3CR1 antibodies were used to stain the subsets of EM CD8+ T cells, while anti-interferon-gamma (IFN-γ), interleukin-17 (IL-17), and forkhead box P3 (FOXP3) antibodies were used for CD4+ T cell subsets.
Results: Of the 47 obese children, 11 were female. Children with MS had significantly higher levels of serum insulin (34.8±13.8 vs. 16.4±6.3 μU/mL, p<0.001) and homeostasis model assessment of insulin resistance (8.9±4.1 vs. 3.9±1.5, p<0.001) than children without MS. Children with MS revealed significantly higher frequencies of IL-7Rαlow CD8+ T cells (60.1 ±19.1% vs. 48.4±11.5%, p=0.047) and IL-7RαlowCX3CR1+ CD8+ T cells (53.8±20.1% vs. 41.5 ±11.9%, p=0.036) than children without MS. As the serum triglyceride levels increased, the frequency of IL-7RαlowCX3CR1+ and IL-7RαhighCX3CR1- CD8+ T cells increased and decreased, respectively (r=0.335, p=0.014 and r=-0.350, p=0.010, respectively), in 47 children. However, no CD4+ T cell subset parameters were significantly different between children with and without MS.
Conclusion: In obese children with MS, the changes in immunity due to changes in EM CD8+ T cells might be related to the morbidity of obesity.

Keywords: CD4; CD8; Child; Hypertriglyceridemia; Metabolic syndrome; Obesity; T-Lymphocytes

DOI: https://doi.org/10.5223/pghn.2021.24.4.377

Nat Rev Cancer. 2021 Jul 29.

The immunological and metabolic landscape in primary and metastatic liver cancer.

Xin Li, Pierluigi Ramadori, Dominik Pfister, Marco Seehawer, Lars Zender, Mathias Heikenwalder.

The liver is the sixth most common site of primary cancer in humans, and generally arises in a background of cirrhosis and inflammation. Moreover, the liver is frequently colonized by metastases from cancers of other organs (particularly the colon) because of its anatomical location and organization, as well as its unique metabolic and immunosuppressive environment. In this Review, we discuss how the hepatic microenvironment adapts to pathologies characterized by chronic inflammation and metabolic alterations. We illustrate how these immunological or metabolic changes alter immunosurveillance and thus hinder or promote the development of primary liver cancer. In addition, we describe how inflammatory and metabolic niches affect the spreading of cancer metastases into or within the liver. Finally, we review the current therapeutic options in this context and the resulting challenges that must be surmounted.

DOI: https://doi.org/10.1038/s41568-021-00383-9

Arterioscler Thromb Vasc Biol. 2021 Jul 29. ATVBAHA120314189

Atherosclerosis Impairs Naive CD4 T-Cell Responses via Disruption of Glycolysis.

Dalia E Gaddis, Lindsey E Padgett, Runpei Wu, Anh Nguyen, Chantel McSkimming, Huy Q Dinh, Daniel J Araujo, Angela M Taylor, Coleen A McNamara, Catherine C Hedrick.

OBJECTIVE: CD4 T cells are important regulators of atherosclerotic progression. The metabolic profile of CD4 T cells controls their signaling and function, but how atherosclerosis affects T-cell metabolism is unknown. Here, we sought to determine the impact of atherosclerosis on CD4 T-cell metabolism and the contribution of such alterations to atheroprogression. Approach and Results: Using PCR arrays, we profiled the expression of metabolism genes in CD4 T cells from atherosclerotic, apolipoprotein-E knockout mice fed a Western diet. These cells exhibited dysregulated expression of genes critically involved in glycolysis and fatty acid degradation, compared with those from animals fed a standard laboratory diet. We examined how T-cell metabolism was changed in standard laboratory diet or Western diet-fed apolipoprotein-E knockout mice or humans by measuring glucose uptake, activation, and proliferation in CD4 T cells. We found that naive CD4 T cells from Western diet-fed apolipoprotein-E knockout mice failed to uptake glucose and thus displayed impaired proliferation and activation, compared with CD4 T cells from standard laboratory diet-fed animals. Similarly, as in mice, we observed that naive CD4 T-cell frequencies were reduced in circulation of human subjects with high cardiovascular disease compared with low cardiovascular disease, as assessed clinically based on medically necessary coronary angiography. Naive T cells from high cardiovascular disease subjects also showed reduced proliferative capacity.
CONCLUSIONS: These results highlight the dysfunctional changes that occur in CD4 T-cell metabolism and immune responses during atherosclerosis. Targeting metabolic pathways within naive CD4 T cells could thus yield novel therapeutic approaches for improving CD4 T-cell responses against atheroprogression.

Keywords: T lymphocytes; atherosclerosis; glucose; laboratories; metabolism

DOI: https://doi.org/10.1161/ATVBAHA.120.314189