In vivo metabolic determinants of T cell aging trajectories

Projektinformationen

IMMAGE

ID Finanzhilfevereinbarung: 101077922

DOI

10.3030/101077922

EK-Unterschriftsdatum 16 Dezember 2022

Startdatum 1 Januar 2023

Enddatum 31 Dezember 2027

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 1 500 000,00

EU-Beitrag

€ 1 500 000,00

Koordiniert durch

TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Israel

Periodic Reporting for period 1 - IMMAGE (In vivo metabolic determinants of T cell aging trajectories)

Berichtszeitraum: 2023-01-01 bis 2025-06-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

T cells comprise the cellular arm of the adaptive immune system, helping to fight infections and maintain tissue health. As we age, T cells become less effective, contributing to organ decline and increasing the risk of age-related diseases.
This project explores how aging of the in vivo microenvironment around T cells influences their aging process. While much research has focused on how T cells themselves change with age, we know less about how aging of their surroundings affects their function. Our goal is to understand how this interaction shapes immune decline and whether it can be reversed.
We investigate two key mechanisms:
1. Loss of metabolic support for T cells
2. Harmful signals from the aging spleen
And test whether restoring these supportive signals or blocking the harmful ones can improve T cell function in aged mice.
By identifying how the aging environment weakens the immune system, our study could lead to new strategies for maintaining immune health and reducing the impact of aging on overall health.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

We discovered that T cells from the spleen and lymph nodes (LNs) in aged mice show significant differences. Those from the spleen exhibit more signs of dysfunction, including reduced survival and ability to multiply. By transferring young T cells into aged mice, we confirmed that the aging spleen environment itself drives many of these changes.
We also identified a key contributor: the breakdown of red blood cells in the aged spleen releases excess iron and heme, which stress T cells and contribute to their dysfunction. Exposure to heme and iron in the microenvironment of the cells leads to the buildup of protective proteins supporting T cells survival, but at the cost of reduced iron availability when needed, impairing immune responses.
To counter these effects, we explored potential interventions. Supplementing iron boosted the ability of aged T cells to multiply and improved vaccine responses in older mice. We are now testing treatments that remove excess heme and iron from the spleen to restore T cell function. These findings could lead to strategies for improving immune health in aging individuals.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

T cell functionality declines with age, leading to impaired immunity against infections, reduced vaccine efficacy, and increased susceptibility to autoinflammatory diseases and malignancies.
The mechanisms driving T cell dysfunction in aging encompass universal hallmarks of cellular aging alongside T cell-specific changes. Recent mouse studies suggest that premature T cell aging accelerates aging phenotypes across multiple organs.

IMMAGE investigates this reciprocal interaction, uncovering how aging host tissues shape T cell aging trajectories.
Our findings reveal a fundamental trade-off between T cell survival and function in the aged host, emphasizing the bidirectional relationship between T cells and their microenvironment.
We demonstrate that the aged spleen milieu actively drives multiple known phenotypic and functional defects of aged T cells.
This work paves the way for novel interventions aimed at rejuvenating immunity in the elderly by mitigating the toxic microenvironment of the spleen.
Moreover, it suggests a unifying mechanism underlying many hallmarks of aged T cells.

A vicious cycle of aging