Calibration of cell-intrinsic interleukin-2 response thresholds guides design of a regulatory T cell biased agonist

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F21%3A00543231" target="_blank" >RIV/61388971:_____/21:00543231 - isvavai.cz</a>

Výsledek na webu

<a href="https://elifesciences.org/articles/65777" target="_blank" >https://elifesciences.org/articles/65777</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.7554/eLife.65777" target="_blank" >10.7554/eLife.65777</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Calibration of cell-intrinsic interleukin-2 response thresholds guides design of a regulatory T cell biased agonist

Popis výsledku v původním jazyce

Interleukin-2 is a pleiotropic cytokine that mediates both pro- and anti-inflammatory functions. Immune cells naturally differ in their sensitivity to IL-2 due to cell type and activation state-dependent expression of receptors and signaling pathway components. To probe differences in IL-2 signaling across cell types, we used structure-based design to create and profile a series of IL-2 variants with the capacity to titrate maximum signal strength in fine increments. One of these partial agonists, IL-2-REH, specifically expanded Foxp3+ regulatory T cells with reduced activity on CD8+ T cells due to cell type-intrinsic differences in IL-2 signaling. IL-2-REH elicited cell typedependent differences in gene expression and provided mixed therapeutic results: showing benefit in the in vivo mouse dextran sulfate sodium (DSS) model of colitis, but no therapeutic efficacy in a transfer colitis model. Our findings show that cytokine partial agonists can be used to calibrate intrinsic differences in response thresholds across responding cell types to narrow pleiotropic actions, which may be generalizable to other cytokine and growth factor systems.

Název v anglickém jazyce

Calibration of cell-intrinsic interleukin-2 response thresholds guides design of a regulatory T cell biased agonist

Popis výsledku anglicky

Interleukin-2 is a pleiotropic cytokine that mediates both pro- and anti-inflammatory functions. Immune cells naturally differ in their sensitivity to IL-2 due to cell type and activation state-dependent expression of receptors and signaling pathway components. To probe differences in IL-2 signaling across cell types, we used structure-based design to create and profile a series of IL-2 variants with the capacity to titrate maximum signal strength in fine increments. One of these partial agonists, IL-2-REH, specifically expanded Foxp3+ regulatory T cells with reduced activity on CD8+ T cells due to cell type-intrinsic differences in IL-2 signaling. IL-2-REH elicited cell typedependent differences in gene expression and provided mixed therapeutic results: showing benefit in the in vivo mouse dextran sulfate sodium (DSS) model of colitis, but no therapeutic efficacy in a transfer colitis model. Our findings show that cytokine partial agonists can be used to calibrate intrinsic differences in response thresholds across responding cell types to narrow pleiotropic actions, which may be generalizable to other cytokine and growth factor systems.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10606 - Microbiology

Projekt

<a href="/cs/project/GA18-12973S" target="_blank" >GA18-12973S: Komplexy IL-2 s muteiny mAb JES6-1 mající různou afinitou k IL-2: hledání varianty s nejvíce selektivní stimulační aktivitou pro Treg buňky in vivo</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

eLife

ISSN

2050-084X

e-ISSN

2050-084X

Svazek periodika

10

Číslo periodika v rámci svazku

MAY 18 2021

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

28

Strana od-do

e65777

Kód UT WoS článku

000653615000001

EID výsledku v databázi Scopus

2-s2.0-85106158874