The aryl hydrocarbon receptor cell intrinsically promotes resident memory CD8+ T cell differentiation and function

Dean, Joseph; Helm, Eric Y.; Fu, Zheng Qing; Xiong, Lifeng; Sun, Na; Oliff, Kristen N.; Muehlbauer, Marcus; Avram, Dorina; Zhou, Liang

doi:10.1016/j.celrep.2022.111963

Cited by 23 publications

(33 citation statements)

References 83 publications

(99 reference statements)

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“…AHR expression and signalling is essential for both TCRab + and TCRgd + IEL survival, maintenance, and effector function (Dean et al, 2023;Li et al, 2011;Panda et al, 2023). In line with these findings, the percentage, and total numbers of natural CD8aa IELs recovered from naïve AHRKO immune mice were significantly lower compared with WT littermates whereas the numbers of TCRab + CD8ab + IELs were similar (Figure 4A-C).…”

Section: Ahr-dependent Cd8a Iels Confer Resistance To C Tyzzeri Infec...supporting

confidence: 76%

“…While the exact mechanism by which these IELs sense epithelial injury during infection is unclear (Hoytema van , being in a constant state of heightened activation with increased cytolytic granzyme expression (Konjar et al, 2018) increases their ability to swiftly act on Cryptosporidiuminfected epithelial cells. The presence of IELs at the coalface of the mucosal barrier and their dependence on AHR (Dean et al, 2023;Li et al, 2011;Panda et al, 2023), opens up the possibility to modulate these IELs during Cryptosporidium infections through supplementation of dietary AHR ligands.…”

Section: Discussionmentioning

confidence: 99%

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Dietary environmental factors shape the immune defence againstCryptosporidiuminfection

Sateriale

Maradana

Marzook

et al. 2023

Preprint

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Cryptosporidium is a leading cause of diarrheal-related deaths in children, especially in resource-poor settings. It also targets the immunocompromised, chronically infecting people living with HIV and primary immunodeficiencies. There is no vaccine or effective treatment. While it is known from human cases and animal models that CD4+ T-cells play a role in curbing Cryptosporidium, the role of CD8+ cells remains to be defined. Using a Cryptosporidium tyzzeri mouse model, we show that gut-resident CD8+ intraepithelial lymphocytes (IELs) confer resistance to parasite growth. CD8+ IELs express, and are dependent on, the ligand-dependent transcription factor aryl hydrocarbon receptor (AHR). AHR deficiency reduced CD8+ IELs, decreased their cytotoxicity, and worsened infection. Transfer of CD8+ IELs rescued severely immunodeficient mice from death following Cryptosporidium challenge. Finally, dietary supplementation of the AHR pro-ligand indole-3-carbinol to new-born mice promoted resistance to infection. Therefore, common dietary metabolites augment the host immune response to cryptosporidiosis, protecting against disease.

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Section: Ahr-dependent Cd8a Iels Confer Resistance To C Tyzzeri Infec...supporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Dietary environmental factors shape the immune defence againstCryptosporidiuminfection

Sateriale

Maradana

Marzook

et al. 2023

Preprint

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“…The suppressed levels of Akkermansia muciniphila in T1DM may therefore be intimately linked to lower shikimate pathway-derived tryptophan (as well as tyrosine and phenylalanine), increased gut permeability, and an altered capacity of the gut microbiome to suppress NK cells and CD8 + T cells. Although AhR activation by kynurenine can induce a state of ‘exhaustion’ in NK cells and CD8 + T cells [ 38 ], the AhR has differential effects in memory CD8 + T cells, with AhR activation suppressing circulating memory CD8 + T cells, while promoting the core gene program of resident memory CD8 + T cells [ 158 ]. As the gut is proposed to be an important site for the inappropriate maintenance of autoreactive memory CD8 + T cells, whereby autoimmune-linked autoreactive CD8 + T cells may interact in the Peyer’s patches of the gut to escape thymic deselection [ 159 ], the effects of enteroviruses and bacteriophages in T1DM pathoetiology may be mediated via suppressed Akkermansia muciniphila levels and shikimate pathway activity.…”

Section: Integrating T1dm Pathogenesis and Pathophysiologymentioning

confidence: 99%

Type I Diabetes Pathoetiology and Pathophysiology: Roles of the Gut Microbiome, Pancreatic Cellular Interactions, and the ‘Bystander’ Activation of Memory CD8+ T Cells

Anderson¹

2023

IJMS

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Type 1 diabetes mellitus (T1DM) arises from the failure of pancreatic β-cells to produce adequate insulin, usually as a consequence of extensive pancreatic β-cell destruction. T1DM is classed as an immune-mediated condition. However, the processes that drive pancreatic β-cell apoptosis remain to be determined, resulting in a failure to prevent ongoing cellular destruction. Alteration in mitochondrial function is clearly the major pathophysiological process underpinning pancreatic β-cell loss in T1DM. As with many medical conditions, there is a growing interest in T1DM as to the role of the gut microbiome, including the interactions of gut bacteria with Candida albicans fungal infection. Gut dysbiosis and gut permeability are intimately associated with raised levels of circulating lipopolysaccharide and suppressed butyrate levels, which can act to dysregulate immune responses and systemic mitochondrial function. This manuscript reviews broad bodies of data on T1DM pathophysiology, highlighting the importance of alterations in the mitochondrial melatonergic pathway of pancreatic β-cells in driving mitochondrial dysfunction. The suppression of mitochondrial melatonin makes pancreatic β-cells susceptible to oxidative stress and dysfunctional mitophagy, partly mediated by the loss of melatonin’s induction of PTEN-induced kinase 1 (PINK1), thereby suppressing mitophagy and increasing autoimmune associated major histocompatibility complex (MHC)-1. The immediate precursor to melatonin, N-acetylserotonin (NAS), is a brain-derived neurotrophic factor (BDNF) mimic, via the activation of the BDNF receptor, TrkB. As both the full-length and truncated TrkB play powerful roles in pancreatic β-cell function and survival, NAS is another important aspect of the melatonergic pathway relevant to pancreatic β-cell destruction in T1DM. The incorporation of the mitochondrial melatonergic pathway in T1DM pathophysiology integrates wide bodies of previously disparate data on pancreatic intercellular processes. The suppression of Akkermansia muciniphila, Lactobacillus johnsonii, butyrate, and the shikimate pathway—including by bacteriophages—contributes to not only pancreatic β-cell apoptosis, but also to the bystander activation of CD8+ T cells, which increases their effector function and prevents their deselection in the thymus. The gut microbiome is therefore a significant determinant of the mitochondrial dysfunction driving pancreatic β-cell loss as well as ‘autoimmune’ effects derived from cytotoxic CD8+ T cells. This has significant future research and treatment implications.

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“…In addition, the AHR might participate in innate immune responses to the microbial invasion of barrier tissues [ 96 ]. Furthermore, the AHR could modify the differentiation and function of both CD4 + T cells and CD8 + T cells [ 97 ], which might be involved in chronic autoimmune damage to CNS neurons [ 98 ] ( Figure 2 ).…”

Section: Kynurenine Metabolites Involved In Brain Memory System and I...mentioning

confidence: 99%

The Tryptophan and Kynurenine Pathway Involved in the Development of Immune-Related Diseases

Tsuji

Ikeda

Yoshikawa

et al. 2023

IJMS

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The tryptophan and kynurenine pathway is well-known to play an important role in nervous, endocrine, and immune systems, as well as in the development of inflammatory diseases. It has been documented that some kynurenine metabolites are considered to have anti-oxidative, anti-inflammatory, and/or neuroprotective properties. Importantly, many of these kynurenine metabolites may possess immune-regulatory properties that could alleviate the inflammation response. The abnormal activation of the tryptophan and kynurenine pathway might be involved in the pathophysiological process of various immune-related diseases, such as inflammatory bowel disease, cardiovascular disease, osteoporosis, and/or polycystic ovary syndrome. Interestingly, kynurenine metabolites may be involved in the brain memory system and/or intricate immunity via the modulation of glial function. In the further deliberation of this concept with engram, the roles of gut microbiota could lead to the development of remarkable treatments for the prevention of and/or the therapeutics for various intractable immune-related diseases.

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The aryl hydrocarbon receptor cell intrinsically promotes resident memory CD8+ T cell differentiation and function

Cited by 23 publications

References 83 publications

Dietary environmental factors shape the immune defence againstCryptosporidiuminfection

Dietary environmental factors shape the immune defence againstCryptosporidiuminfection

Type I Diabetes Pathoetiology and Pathophysiology: Roles of the Gut Microbiome, Pancreatic Cellular Interactions, and the ‘Bystander’ Activation of Memory CD8+ T Cells

The Tryptophan and Kynurenine Pathway Involved in the Development of Immune-Related Diseases

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