In Vitro Generation of Microbe-Specific Human Th17 Cells

Braun, Julia M.; Zielinski, Christina E.

doi:10.1007/978-1-4939-1212-4_10

Cited by 5 publications

(4 citation statements)

References 8 publications

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“…We hypothesized that the priming requirement of naïve T cells for pro-inflammatory IL-1 which we discovered previously (2), renders the emerging C. albicans-specific Th17 cells resistant towards the anti-inflammatory effects of NaCl. We therefore reconstructed C. albicans-specific T cell priming in vitro by coculturing naïve CFSE-labelled T cells and autologous monocytes pulsed with C. albicans in the presence or absence of IL-1 blocking antibodies as described before (2,42). Likewise, S. aureus-specific T cell differentiation was performed in the presence or absence of recombinant IL-1 to assess whether supplementation with exogenous IL-1 renders S. aureus-specific naïve T cells resistant to FoxP3 upregulation during their priming phase.…”

Section: The Antigen Specificity Of Th17 Cells Determines Whether Promentioning

confidence: 99%

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Salt generates antiinflammatory Th17 cells but amplifies pathogenicity in proinflammatory cytokine microenvironments

Matthias¹,

Heink²,

Picard³

et al. 2020

Journal of Clinical Investigation

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T helper cells integrate signals from their microenvironment to acquire distinct specialization programs for efficient clearance of diverse pathogens or for immunotolerance. Ionic signals have recently been demonstrated to affect T cell polarization and function. Sodium chloride (NaCl) was proposed to accumulate in peripheral tissues upon dietary intake and to promote autoimmunity via the Th17 cell axis. Here we demonstrate that high NaCl conditions induced a stable, pathogen-specific, anti-inflammatory Th17 cell fate in human T cells in vitro. The p38/MAPK pathway, involving NFAT5 and SGK1, regulated FoxP3 and interleukin (IL)-17Aexpression in high-NaCl conditions. The NaCl-induced acquisition of an anti-inflammatory Th17 cell fate was confirmed in vivo in an experimental autoimmune encephalomyelitis (EAE) mouse model, which demonstrated strongly reduced disease symptoms upon transfer of T cells polarized in high NaCl conditions. However, NaCl was coopted to promote murine and human Th17 cell pathogenicity, if T cell stimulation occurred in a pro-inflammatory and TGF--low cytokine microenvironment. Taken together, our findings reveal a context-dependent, dichotomous role for NaCl in shaping Th17 cell pathogenicity. NaCl might therefore prove beneficial for the treatment of chronic inflammatory diseases in combination with cytokineblocking drugs.

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Section: The Antigen Specificity Of Th17 Cells Determines Whether Promentioning

confidence: 99%

“…T cell clones were generated in nonpolarizing conditions as described previously following single-cell deposition via flow cytometry-assisted cell sorting or by limiting dilution plating (61). Pathogen-specific T cell clones were generated as described previously (2,42).…”

Section: Cell Purification and Sortingmentioning

confidence: 99%

Salt generates antiinflammatory Th17 cells but amplifies pathogenicity in proinflammatory cytokine microenvironments

Matthias¹,

Heink²,

Picard³

et al. 2020

Journal of Clinical Investigation

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“…pMHC complexes loaded with MART-1 peptide were refolded as described previously (Altman et al, 1996) (Busch et al, 1998) (Garboczi et al, 1996a) (Garboczi et al, 1996b). Antigen-specific T-cell clones were generated as described previously (Braun and Zielinski, 2014; Zielinski et al, 2012).…”

Section: Methodsmentioning

confidence: 99%

Sodium chloride in the tumor microenvironment enhances T-cell metabolic fitness and cytotoxicity

Soll,

Arunkumar,

Alissa-Alkhalaf

et al. 2023

Preprint

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Adoptive T-cell therapy has become a powerful weapon for cancer treatment. The efficacy of antitumor immunity is associated with the metabolic state of cytotoxic T cells, which is highly sensitive to the tumor microenvironment. It is therefore of considerable interest to bypass immunosuppressive signals in the tumor microenvironment and to identify factors that augment cytotoxic effector functions and ultimately tumor killing. Whether ionic signals serve as aberrant immune signals and influence the adaptive human antitumor immune response is still largely unexplored. We therefore investigated the effect of sodium on the phenotype, function and metabolic regulation of human CD8+ T cells using transcriptomic, metabolomic, high-dimensional flow cytometric and functional assays. We demonstrate a significant enrichment of sodium in solid tumors from patients with breast cancer, which leaves a transcriptomic imprint on intratumoral immune cells. Sodium chloride (NaCl) enhanced the activation state and effector functions of human CD8+ memory T cells. These functional alterations were associated with enhanced metabolic fitness, particularly increases in glycolysis, oxidative phosphorylation and overall nutrient uptake. These NaCl-induced effects translated into increased tumor cell killing in vitro and in a tumor mouse model in vivo. We therefore propose NaCl as a positive regulator of acute antitumor immunity that could be harnessed for ex vivo conditioning of adoptively transferred T cells, such as CAR T-cells.

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“…In the absence of IL-1β, sodium chloride has been found to promote an anti-inflammatory Th17 cell identity instead. The differential requirement for IL-1β in the process of Th17 cell priming is contingent on the microbial T cell receptor specificity of the naïve T helper cell [ 60 , 61 , 62 ]. C. albicans -specific Th17 cell differentiation requires IL-1β, whereas S. aureus -specific Th17 cell differentiation is feasible in its absence.…”

Section: Regulation Of Pro- Versus Anti-inflammatory T Cell Functions By Saltmentioning

confidence: 99%

Regulation of T Cell Responses by Ionic Salt Signals

Zielinski

2021

Cells

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T helper cell responses are tailored to their respective antigens and adapted to their specific tissue microenvironment. While a great proportion of T cells acquire a resident identity, a significant proportion of T cells continue circulating, thus encountering changing microenvironmental signals during immune surveillance. One signal, which has previously been largely overlooked, is sodium chloride. It has been proposed to have potent effects on T cell responses in the context of autoimmune, allergic and infectious tissue inflammation in mouse models and humans. Sodium chloride is stringently regulated in the blood by the kidneys but displays differential deposition patterns in peripheral tissues. Sodium chloride accumulation might furthermore be regulated by dietary intake and thus by intentional behavior. Together, these results make sodium chloride an interesting but still controversial signal for immune modulation. Its downstream cellular activities represent a potential therapeutic target given its effects on T cell cytokine production. In this review article, we provide an overview and critical evaluation of the impact of this ionic signal on T helper cell polarization and T helper cell effector functions. In addition, the impact of sodium chloride from the tissue microenvironment is assessed for human health and disease and for its therapeutic potential.

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In Vitro Generation of Microbe-Specific Human Th17 Cells

Cited by 5 publications

References 8 publications

Salt generates antiinflammatory Th17 cells but amplifies pathogenicity in proinflammatory cytokine microenvironments

Salt generates antiinflammatory Th17 cells but amplifies pathogenicity in proinflammatory cytokine microenvironments

Sodium chloride in the tumor microenvironment enhances T-cell metabolic fitness and cytotoxicity

Regulation of T Cell Responses by Ionic Salt Signals

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