T-cells produce acidic niches in lymph nodes to suppress their own effector functions

Wu, Hao; Estrella, Verónica; Beatty, Matthew; Abrahams, Dominique; El-Kenawi, Asmaa; Russell, Shonagh; Ibrahim‐Hashim, Arig; Longo, Dario Livio; Reshetnyak, Yana K.; Moshnikova, Anna; Andreev, Oleg A.; Luddy, Kimberly A.; Damaghi, Mehdi; Kodumudi, Krithika; Pillai, Smitha; Enríquez-Navas, Pedro M.; Pilon‐Thomas, Shari; Swietach, Pawel; Gillies, Robert J.

doi:10.1038/s41467-020-17756-7

Cited by 91 publications

(99 citation statements)

References 63 publications

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“…Hypoxia is a major driving force within the tumor through both HIF-dependent and -independent mechanisms. In addition to the TME, lymph nodes (LNs), wound-healing sites, and bone fractures also have an acidic pH, making them immunosuppressive niches and likely sites of VISTA activity [ 3 , 61 – 63 ]. The paracortical region of the LN is acidic, a possible result of T cell glycolytic activity [ 61 ].…”

Section: Indirect Metabolic Mechanisms That Increase Extracellular Aciditymentioning

confidence: 99%

“…This acidic microenvironment has been shown to inhibit murine CD8 + T cell effector functions and prevent cytokine production at a post-translational step. Once at physiologic pH outside the LN, T cells can regain their functionality [ 61 ]. The acidic pHe in bone fractures is associated with enhanced proinflammatory cytokine and cathepsin B production, leading to acidic pH-dependent osteoblast death [ 63 ].…”

Section: Indirect Metabolic Mechanisms That Increase Extracellular Aciditymentioning

confidence: 99%

“…These are examples where acidic pH appears to downregulate lymphocyte activity to allow normal function and repair of tissue. We hypothesize that selectively manipulating the pH of the TME might be an alternative way to modulate VISTA activity [ 61 , 66 ].…”

Section: Indirect Metabolic Mechanisms That Increase Extracellular Aciditymentioning

confidence: 99%

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VISTA: A Mediator of Quiescence and a Promising Target in Cancer Immunotherapy

Yuan

Tatineni

Mahoney

et al. 2021

Trends in Immunology

105

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V-domain Ig suppressor of T cell activation (VISTA) is a B7 family member that maintains T cell and myeloid quiescence and is a promising target for combination cancer immunotherapy. During inflammatory challenges, VISTA activity reprograms macrophages towards reduced production of proinflammatory cytokines and increased production of interleukin (IL)-10 and other anti-inflammatory mediators. The interaction of VISTA with its ligands is regulated by pH, and the acidic pH ~6.0 in the tumor microenvironment (TME) facilitates VISTA binding to P-selectin glycoprotein ligand 1 (PSGL-1). Targeting intratumoral pH might be a way to reduce the immunoinhibitory activity of the VISTA pathway and enhance antitumor immune responses. We review differences among VISTA therapeutics under development as candidate immunotherapies, focusing on VISTA binding partners and the unique structural features of this interaction.

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Section: Indirect Metabolic Mechanisms That Increase Extracellular Aciditymentioning

confidence: 99%

Section: Indirect Metabolic Mechanisms That Increase Extracellular Aciditymentioning

confidence: 99%

See 1 more Smart Citation

VISTA: A Mediator of Quiescence and a Promising Target in Cancer Immunotherapy

Yuan

Tatineni

Mahoney

et al. 2021

Trends in Immunology

105

View full text Add to dashboard Cite

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“…However, ligands for endosomal or plasma membrane VISTA have not been conclusively demonstrated. It is of interest to note that the lymph node paracortical zones (where CD4 + T cells are enriched) are profoundly acidic, and this acidity is T-cell dependent whereby T cells acidity is a self-regulatory feedback mechanism to inhibit glycolytic rate and suppress the effector T cell response ( 60 ). Whether the acidic environment in certain tissues plays a role in VISTA signaling or function remains unclear.…”

Section: The Vista Ligand: Current State Of the Sciencementioning

confidence: 99%

VISTA: A Target to Manage the Innate Cytokine Storm

et al. 2021

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In recent years, the success of immunotherapy targeting immunoregulatory receptors (immune checkpoints) in cancer have generated enthusiastic support to target these receptors in a wide range of other immune related diseases. While the overwhelming focus has been on blockade of these inhibitory pathways to augment immunity, agonistic triggering via these receptors offers the promise of dampening pathogenic inflammatory responses. V-domain Ig suppressor of T cell activation (VISTA) has emerged as an immunoregulatory receptor with constitutive expression on both the T cell and myeloid compartments, and whose agonistic targeting has proven a unique avenue relative to other checkpoint pathways to suppress pathologies mediated by the innate arm of the immune system. VISTA agonistic targeting profoundly changes the phenotype of human monocytes towards an anti-inflammatory cell state, as highlighted by striking suppression of the canonical markers CD14 and Fcγr3a (CD16), and the almost complete suppression of both the interferon I (IFN-I) and antigen presentation pathways. The insights from these very recent studies highlight the impact of VISTA agonistic targeting of myeloid cells, and its potential therapeutic implications in the settings of hyperinflammatory responses such as cytokine storms, driven by dysregulated immune responses to viral infections (with a focus on COVID-19) and autoimmune diseases. Collectively, these findings suggest that the VISTA pathway plays a conserved, non-redundant role in myeloid cell function.

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“…2). Furthermore, this change in metabolism might also directly influence immune cells since these cells especially T‐cell subpopulations have a different metabolic profile [121,122]. Thereby, ketosis might limit immune activation, which stops the development of fibrosis.…”

Section: Management Of Ptdm: Novel Antidiabeticsmentioning

confidence: 99%

Management of post‐transplant diabetes: immunosuppression, early prevention, and novel antidiabetics

et al. 2020

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Summary Post‐transplant diabetes mellitus (PTDM) shows a relationship with risk factors including obesity and tacrolimus‐based immunosuppression, which decreases pancreatic insulin secretion. Several of the sodium–glucose‐linked transporter 2 inhibitors (SGLT2is) and glucagon‐like peptide 1 receptor agonists (GLP1‐RAs) dramatically improve outcomes of individuals with type 2 diabetes with and without chronic kidney disease, which is, as heart failure and atherosclerotic cardiovascular disease, differentially affected by both drug classes (presumably). Here, we discuss SGLT2is and GLP1‐RAs in context with other PTDM management strategies, including modification of immunosuppression, active lifestyle intervention, and early postoperative insulin administration. We also review recent studies with SGLT2is in PTDM, reporting their safety and antihyperglycemic efficacy, which is moderate to low, depending on kidney function. Finally, we reference retrospective case reports with GLP1‐RAs that have not brought forth major concerns, likely indicating that GLP1‐RAs are ideal for PTDM patients suffering from obesity. Although our article encompasses PTDM after solid organ transplantation in general, data from kidney transplant recipients constitute the largest proportion. The PTDM research community still requires data that treating and preventing PTDM will improve clinical conditions beyond hyperglycemia. We therefore suggest that it is time to collaborate, in testing novel antidiabetics among patients of all transplant disciplines.

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T-cells produce acidic niches in lymph nodes to suppress their own effector functions

Cited by 91 publications

References 63 publications

VISTA: A Mediator of Quiescence and a Promising Target in Cancer Immunotherapy

VISTA: A Mediator of Quiescence and a Promising Target in Cancer Immunotherapy

VISTA: A Target to Manage the Innate Cytokine Storm

Management of post‐transplant diabetes: immunosuppression, early prevention, and novel antidiabetics

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