# Peripheral T cell maintenance defects with aging

> **NIH NIH P01** · UNIVERSITY OF ARIZONA · 2024 · $517,662

## Abstract

PROJECT 3- Abstract
 Naïve T cells (Tn) are produced in the thymus, but require peripheral mechanisms to maintain their
homeostasis and function. The premise of this project is that, while thymic involution is a proximal cause of
reduced Tn numbers with aging, defects in peripheral maintenance mechanisms in secondary lymphoid organs
(SLO) also significantly contribute to immunosenescence. Indeed, in the past project period we have
demonstrated that uncorrected defects in peripheral maintenance of Tn cells can powerfully undermine the
benefits of reawakening T cell production by the rejuvenated thymus. We further pinpointed a precise
chronological sequence of degenerative structural and functional changes in different SLO.
 This renewal application will continue to dissect mechanistic molecular and cellular basis of SLO aging
and regeneration. Based on the order of changes and the evidence supporting cross-talk between Tn cells and
SLO stroma, we hypothesize that reduced thymic production of Tn cells reduces trophic signals to SLO
stroma, leading to initial stromal niche and network disorganization, that in turn deprives Tn cells of
vital trophic signals and initiates a negative feed-forward loop of deterioration in both Tn cell and SLO
stromal responses. Our specific aims are:
 SA1. To elucidate molecular changes in lymph node stroma with aging and IL-7 complex
rejuvenation, using a hierarchy of in vitro and in vivo approaches to test a pipeline of candidates identified by
miniarray and scRNASeq approaches in the past support period; and SA2. To dissect the intrinsic and
extrinsic age-related defects in SLO stromal cells and the role of Tn:stromal crosstalk in LN
homeostasis with aging, by examining the roles of oxidative stress, senescent cell accumulation, persistent
Tn cell influx and natural polymicrobial exposure (to pet store mice) in LN/SLO aging.
Once the defects are dissected, we will formulate interventions that improve peripheral T cell
maintenance in aged organisms. These interventions will be tested by Core D, individually or combined with
thymic rejuvenation treatments coming from P1&2, for the ability to improve protective immunity against
infection. Together with powerful analytical pipelines from Cores A&B, as well as human molecular target
verification by Core C, that will correlate age-related changes in mouse T cell and lymphoid organ aging to
those in humans, this will provide direct preclinical data that are expected to pave the way for human T cell
rejuvenation in older adults.

## Key facts

- **NIH application ID:** 10851687
- **Project number:** 5P01AG052359-07
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** JANKO Z. NIKOLICH
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $517,662
- **Award type:** 5
- **Project period:** 2017-09-15 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10851687

## Citation

> US National Institutes of Health, RePORTER application 10851687, Peripheral T cell maintenance defects with aging (5P01AG052359-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10851687. Licensed CC0.

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