Sepsis expands a CD39+ plasmablast population that promotes immunosuppression via adenosine-mediated inhibition of macrophage antimicrobial activity

Nascimento, Daniele C.; Viacava, Paula Ramos; Ferreira, Raphael Gomes; Damaceno, Marina Alves; Piñeros, Annie R.; Melo, Paulo H.; Donate, Paula B.; Toller-Kawahisa, Juliana E; Zoppi, Daniel; Veras, Flávio P.; Peres, Raphael Sanches; Menezes-Silva, Luísa; Caetité, Diego B; Oliveira, Antônio Edson Rocha; Castro, Ícaro Maia Santos de; Kauffenstein, Gilles; Nakaya, Helder I.; Borges, Marcos C.; Zamboni, Dario S.; Fonseca, Denise Morais da; Paschoal, Jonas Augusto Rizzato; Cunha, Thiago M.; Quesniaux, Valérie; Linden, Joel; Cunha, Fernando Q.; Ryffel, Bernhard; Alves‐Filho, José C.

doi:10.1016/j.immuni.2021.08.005

Cited by 54 publications

(57 citation statements)

References 61 publications

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“…Indeed, ADORA2b-deficient macrophages exhibit increased bacteria phagocytosis capacity, while ADORA2bKO mice show decreased peritoneal bacterial load and improved survival in a CLP model of sepsis [ 121 ]. Likewise, accumulation of adenosine by expanded CD39 + plasmablast subpopulation impairs macrophage bacterial killing and promotes IL-10 production via ADORA2a signaling in septic mice [ 122 ]. Besides, employing this mouse model of sepsis, Haskó and colleagues describe a protective role of P2X7R in macrophages by diminishing bacterial load and production of pro-inflammatory cytokines and chemokines, as well as improving mouse survival [ 123 ].…”

Section: Bacterial Infectionsmentioning

confidence: 99%

Purinergic modulation of the immune response to infections

Eberhardt

Bergero

Mariotta

et al. 2022

Purinergic Signalling

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Infectious diseases are caused by the invasion of pathogenic microorganisms such as fungi, bacteria, viruses, and parasites. After infection, disease progression relies on the complex interplay between the host immune response and the microorganism evasion strategies. The host’s survival depends on its ability to mount an efficient protective anti-microbial response to accomplish pathogen clearance while simultaneously preventing tissue injury by keeping under control the excessive inflammatory process. The purinergic system has the dual function of regulating the immune response and triggering effector antimicrobial mechanisms. This review provides an overview of the current knowledge of the modulation of innate and adaptive immunity driven by the purinergic system during parasitic, bacterial and viral infections.

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Section: Bacterial Infectionsmentioning

confidence: 99%

Purinergic modulation of the immune response to infections

Eberhardt

Bergero

Mariotta

et al. 2022

Purinergic Signalling

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“…The specialized adaptive sub-lineages of Regulatory T and B lymphocytes, which possess CD39/CD73 ectonucleotidase complexes, suppress effector cells by generating adenosine ( Antonioli et al., 2013 ). Sepsis-survival models of Legionella pneumophila infection exhibited increased CD39-expressing B cells, elevated extracellular adenosine and impaired bacterial killing ( Nascimento et al., 2021 ). In this model, adenosine-mediated inhibition of splenic macrophages relied on both CD39, for adenosine synthesis, and A 2A for adenosine binding.…”

Section: Adenosine Mediates Pro and Anti-inflammatory Cascadesmentioning

confidence: 99%

“…In this model, adenosine-mediated inhibition of splenic macrophages relied on both CD39, for adenosine synthesis, and A 2A for adenosine binding. In CD39 deficient (Ent-/-) mice or with the blockade or deletion of A 2A there was both reduced bacterial burden and enhanced host resistance to L. pneumophila in spleen and lung ( Nascimento et al., 2021 ).…”

Section: Adenosine Mediates Pro and Anti-inflammatory Cascadesmentioning

confidence: 99%

Anti-Inflammatory Metabolites in the Pathogenesis of Bacterial Infection

Urso

Prince

2022

Front. Cell. Infect. Microbiol.

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Host and pathogen metabolism have a major impact on the outcome of infection. The microenvironment consisting of immune and stromal cells drives bacterial proliferation and adaptation, while also shaping the activity of the immune system. The abundant metabolites itaconate and adenosine are classified as anti-inflammatory, as they help to contain the local damage associated with inflammation, oxidants and proteases. A growing literature details the many roles of these immunometabolites in the pathogenesis of infection and their diverse functions in specific tissues. Some bacteria, notably P. aeruginosa, actively metabolize these compounds, others, such as S. aureus respond by altering their own metabolic programs selecting for optimal fitness. For most of the model systems studied to date, these immunometabolites promote a milieu of tolerance, limiting local immune clearance mechanisms, along with promoting bacterial adaptation. The generation of metabolites such as adenosine and itaconate can be host protective. In the setting of acute inflammation, these compounds also represent potential therapeutic targets to prevent infection.

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“…In this study, we clearly demonstrate terminally exhausted CD8 + T cells, a common cellular fate of CD8+ T cells in solid tumors, upregulate the ectonucleotidase CD39 upon hypoxia exposure to levels sufficient to create a tolerogenic microenvironment. CD39 is a well characterized immunosuppressive molecule 25,35,48,67,68 , and indeed recent efforts to therapeutically block CD39 and CD73 in combination with checkpoint blockade have yielded impressive results 37,38,69 . Here, we delineate a specific role of CD39 on tT exh cells, revealing that CD8 + T cell-restricted deletion 8 of CD39 alone results in retained polyfunctionality in tumor-infiltrating T cells and a slowed tumor progression.…”

Section: Tt Exh Cells Are Functionally Significant Suppressors In Tumorsmentioning

confidence: 99%

Tumor hypoxia drives suppressor function in exhausted T cells limiting antitumor immunity

Delgoffe

Vignali

DePeaux

et al. 2021

Preprint

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While CD8+ cytotoxic T cells are clearly critical for identification and elimination of cancer cells, factors concentrated within the tumor microenvironment drive their altered differentiation to a hypofunctional, short-lived state termed exhaustion. Exhaustion is a progressive lineage, and it is now clear that the most terminally exhausted T (tTexh) cells are not the targets of checkpoint blockade immunotherapy but rather serve as factors that limit immunotherapeutic efficacy. Compared directly, tumor-infiltrating CD8+ tTexh cells bear notable phenotypic similarity to CD4+Foxp3+ regulatory T (Treg) cells, suggesting beyond loss of proinflammatory function, tTexh cells may be directly anti-functional and constrain tumor specific immunity. Here we show, when isolated from the same tumor microenvironment, terminally exhausted CD8+ T cells carried similar capacity to suppress T cell proliferation as CD4+Foxp3+ Treg cells. Unlike Treg cells, tTexh cells suppress solely via the ectonucleotidase CD39, which serves to deplete extracellular ATP (eATP) and produce an adenosinergic environment. CD39 expression in tTexh cells is driven by exposure to tumor hypoxia, such that therapeutic targeting of hypoxia limits tTexh suppression and support responses to immunotherapy. Specific deletion of CD39 in CD8+ T cells slows tumor progression and improves response to checkpoint blockade, highlighting a major role for immunosuppression by exhausted T cells in cancer. Thus, tTexh cells are an unappreciated immunoregulatory population and for full immunotherapeutic efficacy, strategies should be designed to either limit their generation, reprogram their immunosuppressive nature, or remove them from the tumor microenvironment.

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Sepsis expands a CD39+ plasmablast population that promotes immunosuppression via adenosine-mediated inhibition of macrophage antimicrobial activity

Cited by 54 publications

References 61 publications

Purinergic modulation of the immune response to infections

Purinergic modulation of the immune response to infections

Anti-Inflammatory Metabolites in the Pathogenesis of Bacterial Infection

Tumor hypoxia drives suppressor function in exhausted T cells limiting antitumor immunity

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