In vivo metabolic determinants of T cell aging trajectories

Introduction

T lymphocytes play a central role in the immune defense against intruders and support tissue homeostasis and function. Strikingly, an aged or dysfunctional T cell immunity is sufficient to promote organ aging and multiple age-related morbidities.

Hypothesis

In this proposal, we hypothesize that there is a bidirectional relationship between T cells and their in vivo microenvironment that could develop into a vicious cycle under conditions of aging and disease.

Current Understanding

While a lot is known about the cellular mechanisms underlying T cell dysfunction with age, a profound understanding of how aging of the microenvironment impacts T cell immunity is missing. This work directly targets this gap to determine how the in vivo microenvironment in an aged mouse dictates T cell aging trajectories.

Mechanisms of Study

Following on our preliminary findings, we will study two major mechanisms:

1. Deficient Metabolic Support: We propose novel mechanisms by which stromal cells in the T cell zone of secondary lymphoid organs provide T cells metabolic needs for activation, and its failure in aged lymph nodes.
2. Toxic Signals: We will investigate toxic signals specific to the aged spleen that inhibit T cell metabolism and activation.

Targeting Pathways

Finally, we will investigate whether targeting these pathways would rejuvenate T cell immunity in vivo. The proposed study will discover unknown mechanisms supporting T cell metabolism in situ and will provide a causative link between T cell aging phenotypes and aging of their microenvironment.

Implications

Finding new ways to rejuvenate immunity holds the promise for comprehensive and simultaneous targeting of multiple age-related pathologies.