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The role of lymph node structural organization in naïve T cell decline with age

Award Number: R01AG080037
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028
AWARD TERMINATION DATE: 05/05/2025

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The role of lymph node structural organization in naïve T cell decline with age - PROJECT SUMMARY/ABSTRACT The project goal is to understand how age-associated changes to the lymph nodes contribute to decreased survival of naïve T cells, a hallmark of immune aging. Naïve T cells are essential for resolving infections caused by newly encountered pathogens, but their number and frequency within the T cell population decrease dramatically with age. This contributes to reduced magnitude and delayed timing of the aged immune response against infectious disease. Naïve T cell survival requires constant signaling from the tissue environment, and it has been well-supported that the aged environment is defective in its ability to maintain naïve T cell homeostasis. Naïve T cells primarily interact with the tissues of the lymph nodes, organized tissue compartments strategically located throughout the body that serve as coordination centers for the immune response. Broad changes to the size and structure of the lymph nodes have been described with age, for both mice and humans; however, the mechanisms driving these changes, and how they impact naïve T cells, are unknown. Our data have revealed changes with age to the lymph node stromal cell type known as the fibroblastic reticular cell (FRC). Naïve T cells adhere to FRCs and crawl along the FRC network to navigate the lymph nodes. FRCs differentiate in situ in a process that requires continuous lymphotoxin-beta (LTβ) signaling. Mature FRCs express homeostatic cytokines that are essential for naive T cell survival and chemokines that promote interactions and motility within the lymph nodes. Homeostatic chemokines such as CCL21 have well-appreciated roles in promoting naïve T cell recruitment to and migration within the lymph nodes, but how their expression and distribution are impacted by age is not clear. In our preliminary work, we determined that lymph node stromal expression of Ltbr (lymphotoxin- beta receptor) and Ccl21 were significantly decreased with age. We also found evidence that FRC differentiation is impaired with age, in that early FRC precursors were decreased in frequency, and that there was an accumulation intermediate FRC precursors. The perturbation to FRC precursors was correlated to decreased expression of LTBR, suggesting that aged FRC precursors were unable to receive the LTβ signals necessary to complete maturation. We hypothesize that with impaired FRC differentiation, FRCs become fibrotic and spatially redistributed within the lymph node, which inhibits the interactions necessary for naïve T cell survival. In this project we will determine the role of age-associated inflammation in impairing signals through LTβR and promoting lymph node fibrosis (Aim 1), and whether increased fibrosis of the lymph node microenvironment impairs naïve T cell survival (Aim 2). Our experimental approach uses live-cell 2-photon microscopy, which enables us to visualize the interaction of naïve T cells with FRCs in real time within intact tissues. The completion of the project will support a mechanism by which the aged tissue microenvironment drives the attrition of naïve T cells. Establishing this link can lead to development of therapeutics to restore the aged lymph node stroma and promote the survival and function of naïve T cells in older individuals.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $591,539 )
2026	2026	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Aging Research	000	4	4/9/2026	NON-COMPETING CONTINUATION	$591,539
														Subtotal = $591,539

Issue Date FY: 2025 ( Subtotal = $579,709 )
2025	2025	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Aging Research	002	3	6/18/2025	NON-COMPETING CONTINUATION	$47,324
2025	2025	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Aging Research	000	3	4/11/2025	NON-COMPETING CONTINUATION	$532,385
2025	2024	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Aging Research	001	2	5/5/2025	TERMINATION	$0
														Subtotal = $579,709

Issue Date FY: 2024 ( Subtotal = $657,565 )
2024	2024	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Aging Research	001	2	7/26/2024	SUPPLEMENT FOR EXPANSION	$66,026
2024	2024	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Aging Research	000	2	5/2/2024	NON-COMPETING CONTINUATION	$591,539
														Subtotal = $657,565

Issue Date FY: 2023 ( Subtotal = $591,539 )
2023	2023	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Aging Research	000	1	7/20/2023	NEW	$591,539
														Subtotal = $591,539

Grand Total All Awards = $2,420,352

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The role of lymph node structural organization in naïve T cell decline with age

Award Number: R01AG080037

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

AWARD TERMINATION DATE: 05/05/2025

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