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ONLINE COVER IL-2 Mutein Passes an Acid Test. This month’s cover depicts a glycolytic tumor releasing lactic acid molecules, establishing an acidic tumor microenvironment (TME). The low pH of the TME suppresses antitumor immune responses and favors tumor growth. Gaggero and Martinez-Fabregas et al. report that cytokines are extremely sensitive to the acidic pH found in tumors and lymph nodes. The activity of IL-2, a cytokine central to T cell responses, is highly limited at acidic pH. Using in vitro evolution, they identify a new IL-2 variant, Switch-2, that exhibits enhanced activity at acidic pH but, surprisingly, exhibits reduced activity at the neutral pH found in healthy tissue. Switch-2 therapy in mice triggered potent antitumor responses while avoiding the severe systemic toxicity associated with current high-dose IL-2 therapies.

Credit: Paul K. Fyfe

Science Immunology

  • Volume 7|
  • Issue 78|
  • Dec 2022

ONLINE COVER IL-2 Mutein Passes an Acid Test. This month’s cover depicts a glycolytic tumor releasing lactic acid molecules, establishing an acidic tumor microenvironment (TME). The low pH of the TME suppresses antitumor immune responses and favors tumor growth. Gaggero and Martinez-Fabregas et al. report that cytokines are extremely sensitive to the acidic pH found in tumors and lymph nodes. The activity of IL-2, a cytokine central to T cell responses, is highly limited at acidic pH. Using in vitro evolution, they identify a new IL-2 variant, Switch-2, that exhibits enhanced activity at acidic pH but, surprisingly, exhibits reduced activity at the neutral pH found in healthy tissue. Switch-2 therapy in mice triggered potent antitumor responses while avoiding the severe systemic toxicity associated with current high-dose IL-2 therapies.

Credit: Paul K. Fyfe

Focus

  • BY
    • James M. Gardner
    • Adrian Liston
  • NO ACCESS
Recent studies shed light on new populations and potential roles of Aire+ and RORγt+ antigen-presenting cells – including unique subsets with surprising properties – in immune homeostasis and host-microbe interactions.

Research Articles

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Immune recall in vaccination and infection confers greater antibody durability and breadth to SARS-CoV-2 variants.
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Loss of Usp22 elicits a cellular and molecular program of emergency hematopoiesis and enhances innate protection in vivo.
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  • NO ACCESS
Epiregulin is an EGFR ligand produced by DC3 dendritic cells that is essential for persistence of skin and lung fibrosis.
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TRIFosome formation in neutrophils and macrophages mediates TNF-induced lethality.
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    • Rafi Ahmed
    • Vaiva Vezys
    • Jasdave S. Chahal
    • David Masopust
  • NO ACCESS
Intramuscular mRNA vaccination induces pulmonary resident memory T cells that can be further expanded with intranasal boosting.
  • BY
    • Egle Kvedaraite
    • Paul Milne
    • Ahad Khalilnezhad
    • Marion Chevrier
    • Raman Sethi
    • Hong Kai Lee
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    • Tatiana von Bahr Greenwood
    • Natalia Mouratidou
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    • Nicole Yee Shin Lee
    • Lara Minnerup
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    • You Yi Hwang
    • Josephine Lum
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    • Weili Xu
    • Anastasia Resteu
    • Hong Liang Tey
    • Ng Lai Guan
    • Anis Larbi
    • Shanshan Wu Howland
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    • Samir E. L. Andaloussi
    • Jorge Braier
    • Georgios Rassidakis
    • Laura Galluzzo
    • Andrzej Dzionek
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    • Jinmiao Chen
    • Matthew Collin
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  • NO ACCESS
Langerhans cell histiocytosis lesions depend on Notch-mediated cooperation between distinct lineages with DC2 and DC3/monocyte features.
  • BY
    • Silvia Gaggero
    • Jonathan Martinez-Fabregas
    • Adeline Cozzani
    • Paul K. Fyfe
    • Malo Leprohon
    • Jie Yang
    • F. Emil Thomasen
    • Hauke Winkelmann
    • Romain Magnez
    • Alberto G. Conti
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    • Suman Mitra
  • NO ACCESS
An engineered pH-selective IL-2 mutein augments cancer immunity in the acidic tumor microenvironment with limited systemic toxicity.
  • BY
    • Graeme P. Sullivan
    • Pavel Davidovich
    • Natalia Muñoz-Wolf
    • Ross W. Ward
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    • NO ACCESS
    IL-37 exhibits pro-inflammatory activity via IL-36 receptor activation.

    Editors' Choice

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    Reports

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    • Open Access
    Durable T cell responses with Omicron cross-recognition are observed after complete and booster vaccination with different COVID-19 vaccines.
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      • Carla Iris Cadima Couto
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    • Open Access
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