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Reaction wavefront theory of notochord segment patterning

Andrew Charles Oates

The vertebrate axis is segmented into repetitive structures, the vertebrae. In fish, these segmented structures are thought to form from the paraxial mesoderm and the adjacent notochord. Recent work revealed an autonomous patterning mechanism in the zebrafish notochord, with inputs from the segmented paraxial mesoderm. The notochord pattern is established in a sequential manner, progressing from anterior to posterior. Building on this previous work, here, we propose a reaction wavefront theory describing notochord patterning in zebrafish. The pattern is generated by an activator-inhibitor reaction-diffusion mechanism. Cues from the paraxial mesoderm are introduced as a profile of inhibitor sinks. Reactions are turned on by a wavefront that advances from anterior to posterior. We show that this reaction wavefront ensures that a pattern is formed sequentially, in register with the cues, despite the presence of fluctuations. We find that the velocity and shape of the reaction wavefront can modulate the prevalence of defective patterns. Normal patterning is supported in a wide range of sink profile wavelengths, while a minimum sink strength is required for the pattern to follow the cues. The theory predicts that distinct defect types occur for small or large wavelengths. Thus, the reaction wavefront theory provides a possible scenario for notochord patterning, with testable predictions that prompt future experiments.

FRONTIERS MEDIA SA2022

PD-1-cis IL-2R agonism yields better effectors from stem-like CD8(+) T cells

Douglas Hanahan, Maria Karagianni, Petra Catalina Schwalie, Mélanie Louise Tichet, Stephan Wullschleger

Expansion and differentiation of antigen-experienced PD-1(+)TCF-1(+) stem-like CD8(+) T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade(1-4). Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of 'better effector' CD8(+) T cells similar to those generated in an acute infection(5). IL-2 binding to the IL-2 receptor alpha-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor beta- and gamma-chain (IL-2R beta gamma)-biased agonists are currently being developed(6-10). Here we show that IL-2R beta gamma-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cis to PD-1. Cis binding of PD1-IL2v to PD-1 and IL-2R beta gamma on the same cell recovers the ability to differentiate stem-like CD8(+) T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.

NATURE PORTFOLIO2022

Generation of a Gal4-dependent gene recombination and illuminating mouse

Freddy Radtke

Cell labeling technologies, including the Cre/loxP system, are powerful tools in developmental biology. Although the conventional Cre/loxP system has been extensively used to label the expression of specific genes, it is less frequently used for labeling protein-protein interactions owing to technical difficulties. In the present study, we generated a new Gal4-dependent transgenic reporter mouse line that expressed Cre recombinase and a nearinfrared fluorescent protein, miRFP670. To examine whether this newly generated transgenic mouse line is applicable in labeling of protein-protein interaction, we used a previously reported transgenic mouse lines that express Notch1 receptor with its intracellular domain replaced with a yeast transcription factor, Gal4. Upon the binding of this artificial Notch1 receptor and endogenous Notch1 ligands, Gal4 would be cleaved from the cell membrane to induce expression of Cre recombinase and miRFP670. Indeed, we observed miRFP670 signal in the mouse embryos (embryonic day 14.5). In addition, we examined whether our Cre recombinase was functional by using another transgenic mouse line that express dsRed after Cre-mediated recombination. We observed dsRed signal in small intestine epithelial cells where Notch1 signal was suggested to be involved in the crypt stem cell maintenance, suggesting that our Cre recombinase was functional. As our newly generated mouse line required only the functioning of Gal4, it could be useful for labeling several types of molecular activities in vivo.

INT PRESS EDITING CENTRE INC2022

PD-1-cis IL-2R agonism yields better effectors from stem-like CD8(+) T cells

Douglas Hanahan, Maria Karagianni, Petra Catalina Schwalie, Mélanie Louise Tichet, Stephan Wullschleger

NATURE PORTFOLIO2022