Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Lymph node structure and function in tolerance: Role of Fibroblastic Reticular Cells

Award Number: R01AI200893
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/13/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

Group Awards By:

View Award Description

Lymph node structure and function in tolerance: Role of Fibroblastic Reticular Cells - Project Summary/Abstract My laboratory has contributed to the better understanding of the mechanisms by which lymph node (LN) stroma controls transplant tolerance. We devoted much effort to defining specific compartments of the LN where Foxp3+ regulatory T cells (Treg) are induced and activated. During costimulatory blockade induced tolerance, naïve T cells migrate through the high endothelial venules (HEV) to the cortical ridge (CR), the region surrounding the HEV, where they are stimulated by alloantigen presenting plasmacytoid dendritic cells (pDC) and differentiate to induced Foxp3+CD4+ regulatory T cells (iTregs). Thus, a unique LN microstructural niche generates tolerance and Tregs. Our overall hypothesis is this niche is required for tolerance, and our goal is to define the key events and structures that regulate this LN domain to manipulate immunity. In this specialized niche, we showed stromal fiber laminin α4:α5 (Lama4:5) ratios determine alloantigen responses. Laminins surrounding the HEV and CR directly instruct T cell entry and conversion to iTregs, with a high Lama4:5 ratio favoring tolerance. Lama4 promotes Foxp3 expression and T cell migration into the HEV and CR, while inhibiting effector T cell differentiation. In contrast, Lama5 inhibits migration, yet stimulates T cell proliferation and Th17. Since fibroblastic reticular cells (FRC) produce stroma, we developed Pdgrfb2-Cre x lama5fl/fl mice (FRC Lama5 KO), in which Lama5 is deficient in LN FRC. Lama5 KO have increased Lama4:5, more Tregs in the CR, and prolonged cardiac graft survival. We also created a new strain of laminin α4fl/fl mice (FRC Lama4 KO) which have decreased Lama4:5, fewer Tregs, and impaired allograft survival. Our new studies now show three novel mechanisms by which FRC regulate tolerance and immunity. First, FRC Lama4 KO mice have expanded Foxp3+CD8+ Tregs, and Lama5 directly stimulates the induction of this poorly characterized CD8+ Treg subset. Second, our prior studies showed FRC CD40 upregulated T cell activation during immunity. Our new studies using FRC CD40 KO show that FRC CD40 also upregulates tolerogenic LN structure and function, including CD4+ Tregs and the Lama4:5 ratio; and FRC CD40 KO mice are resistant to anti-CD40L induced tolerance. Third, FRC are exquisitely sensitive to prior inflammatory events, inducing ‘immunologic scarring’ or changes in LN Lama4:5 structure and function that impair tolerance and limit graft survival. These new data support the specific hypothesis that FRC integrate immune cues to regulate LN laminin niche structure and function, and control immune fate toward inflammation and immunity (low Lama4:5) or toward suppression and tolerance (high Lama4:5). We propose the following aims: Aim 1. Demonstrate mechanisms by which FRC and laminins induce Foxp3+ CD8+ Tregs; Aim 2. Define mechanisms by which CD40 on FRCs regulate T cell alloimmunity; and Aim 3. Define how inflammatory LN niches induced prior to transplant prevent graft survival. The Aims define unique and novel FRC mechanisms. The Aims will synergistically inform, yet do not strictly depend on, each other.


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 = $564,436 )
2026	2026	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	1	7/13/2026	NEW	$564,436
														Subtotal = $564,436

Grand Total All Awards = $564,436

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Lymph node structure and function in tolerance: Role of Fibroblastic Reticular Cells

Award Number: R01AI200893

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/13/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer