AhR activation increases IL‐2 production by alloreactive CD4+ T cells initiating the differentiation of mucosal‐homing Tim3+Lag3+ Tr1 cells

Ehrlich, Allison; Pennington, Jamie; Tilton, Susan C.; Wang, Xisheng; Marshall, Nikki B.; Rohlman, Diana; Funatake, Castle; Punj, Sumit; O’Donnell, Edmond F.; Yu, Zhen; Kolluri, Siva Kumar; Kerkvliet, Nancy I.

doi:10.1002/eji.201747121

Cited by 28 publications

(35 citation statements)

References 55 publications

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“…Higher VZV-Treg and gE-Tcheck percentages at PMR in HZ/ su compared with ZV recipients are also probably related to the higher memory responses in HZ/su. Tregs and Tcheck may play a role in Th1 differentiation by directing the immune response from effector to memory (30)(31)(32). Alternatively, they may signal that Teff cells are being quenched.…”

Section: Resultsmentioning

confidence: 99%

Th1 memory differentiates recombinant from live herpes zoster vaccines

Levin¹,

Kroehl²,

Johnson³

et al. 2018

Journal of Clinical Investigation

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The adjuvanted varicella-zoster virus (VZV) glycoprotein E (gE) subunit herpes zoster vaccine (HZ/su) confers higher protection against HZ than the live attenuated zoster vaccine (ZV). To understand the immunologic basis for the different efficacies of the vaccines, we compared immune responses to the vaccines in adults 50 to 85 years old. gE-specific T cells were very low/undetectable before vaccination when analyzed by FluoroSpot and flow cytometry. Both ZV and HZ/su increased gE-specific responses, but at peak memory response (PMR) after vaccination (30 days after ZV or after the second dose of HZ/su), gE-specific CD4+ and CD8+ T cell responses were 10-fold or more higher in HZ/su compared with ZV recipients. Comparing the vaccines, T cell memory responses, including gE-IL-2+ and VZV-IL-2+ spot-forming cells (SFCs), were higher in HZ/su recipients and cytotoxic and effector responses were lower. At 1 year after vaccination, all gE-Th1 and VZV-IL-2+ SFCs remained higher in HZ/su compared with ZV recipients. Mediation analyses showed that IL-2+ PMR were necessary for the persistence of Th1 responses to either vaccine and VZV-IL-2+ PMR explained 73% of the total effect of HZ/su on persistence. This emphasizes the biological importance of the memory responses, which were clearly superior in HZ/su compared with ZV participants.

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Section: Resultsmentioning

confidence: 99%

Th1 memory differentiates recombinant from live herpes zoster vaccines

Levin¹,

Kroehl²,

Johnson³

et al. 2018

Journal of Clinical Investigation

View full text Add to dashboard Cite

show abstract

“…It is well known that AhR activation by immunosuppressive ligands promotes the development of Foxp3 + Treg cells (33). However, much is unknown concerning the development of AhR-induced Tr1 cells (34). One study showed that Tr1 but not Foxp3 + Treg cells suppress immune activation via an IL-10-dependent mechanism (35).…”

Section: Discussionmentioning

confidence: 99%

Selective AhR knockout in langerin-expressing cells abates Langerhans cells and polarizes Th2/Tr1 in epicutaneous protein sensitization

Hong

Lin

Clausen

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The aryl hydrocarbon receptor (AhR) represents an environmental sensor regulating immune responses. In the skin, AhR is expressed in several cell types, including keratinocytes, epidermal Langerhans cells (LC), and dermal dendritic cells (DC). The mechanisms how AhR activates or inhibits cutaneous immune responses remain controversial, owing to differences in the cell-specific functions of AhR and the different activating ligands. Therefore, we sought to investigate the role of AhR in LC and langerin+and negative DC in the skin. To this aim, we generated Langerin-specific and CD11c-specific knockout (−/−) mice lacking AhR, respectively, in LC and Langerin+dermal DC and in all CD11c+cells. These were then tested in an epicutaneous protein (ovalbumin, Ova) sensitization model. Immunofluorescence microscopy and flow cytometry revealed that Langerin-AhR−/−but not CD11c-AhR−/−mice harbored a decreased number of LC with fewer and stunted dendrites in the epidermis as well as a decreased number of LC in skin-draining lymph nodes (LN). Moreover, in the absence of AhR, we detected an enhanced T helper type-2 (Th2) [increased interleukin 5 (IL-5) and interleukin 13 (IL-13)] and T regulatory type-1 (Tr1) (IL-10) response when LN cells were challenged with Ova in vitro, though the number of regulatory T cells (Treg) in the LN remained comparable. Langerin-AhR−/−mice also exhibited increased blood levels of Ova-specific immunoglobulin E (IgE). In conclusion, deletion of AhR in langerin-expressing cells diminishes the number and activation of LC, while enhancing Th2 and Tr1 responses upon epicutaneous protein sensitization.

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“…AhR also promotes HIF1-α degradation and takes control of Tr1 cell metabolism [ 92 ]. In addition, AhR activation can also initiate the differentiation of mucosal-homing Tim3 + Lag3 + Tr1 cells [ 107 ]. Thus, Trp metabolites promote the differentiation and function of not only Treg cells but also other regulatory T cells, such as Tr1 cells.…”

Section: Regulation Of Trp Metabolites From Gut Microbiota In the Imm...mentioning

confidence: 99%

Gut Microbiota-Derived Tryptophan Metabolites Maintain Gut and Systemic Homeostasis

Gao

Yang

2022

Cells

154

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Tryptophan is an essential amino acid from dietary proteins. It can be metabolized into different metabolites in both the gut microbiota and tissue cells. Tryptophan metabolites such as indole-3-lactate (ILA), indole-3-acrylate (IAC), indole-3-propionate (IPA), indole-3-aldehyde (IAID), indoleacetic acid (IAA), indole-3-acetaldehyde and Kyn can be produced by intestinal microorganisms through direct Trp transformation and also, partly, the kynurenine (Kyn) pathway. These metabolites play a critical role in maintaining the homeostasis of the gut and systematic immunity and also potentially affect the occurrence and development of diseases such as inflammatory bowel diseases, tumors, obesity and metabolic syndrome, diseases in the nervous system, infectious diseases, vascular inflammation and cardiovascular diseases and hepatic fibrosis. They can not only promote the differentiation and function of anti-inflammatory macrophages, Treg cells, CD4+CD8αα+ regulatory cells, IL-10+ and/or IL-35+B regulatory cells but also IL-22-producing innate lymphoid cells 3 (ILC3), which are involved in maintaining the gut mucosal homeostasis. These findings have important consequences in the immunotherapy against tumor and other immune-associated diseases. We will summarize here the recent advances in understanding the generation and regulation of tryptophan metabolites in the gut microbiota, the role of gut microbiota-derived tryptophan metabolites in different immune cells, the occurrence and development of diseases and immunotherapy against immune-associated diseases.

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AhR activation increases IL‐2 production by alloreactive CD4⁺ T cells initiating the differentiation of mucosal‐homing Tim3⁺Lag3⁺ Tr1 cells

Cited by 28 publications

References 55 publications

Th1 memory differentiates recombinant from live herpes zoster vaccines

Th1 memory differentiates recombinant from live herpes zoster vaccines

Selective AhR knockout in langerin-expressing cells abates Langerhans cells and polarizes Th2/Tr1 in epicutaneous protein sensitization

Gut Microbiota-Derived Tryptophan Metabolites Maintain Gut and Systemic Homeostasis

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