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Development, stability, and antigen specificity of T follicular regulatory phenotype cells

Award Number: F31AI186394
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 11/01/2024
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Development, stability, and antigen specificity of T follicular regulatory phenotype cells - PROJECT SUMMARY/ABSTRACT Many human autoimmune diseases are associated with the expansion of self-reactive B cells and subsequent autoantibodies targeting self-constituents. Even in healthy individuals, an appreciable fraction of self-reactive B cells exists, implying the existence of extrinsic layers that restrain overt humoral autoimmunity. Foxp3+ T follicular regulatory (Tfr) cells—defined in part by their localization within the B cell follicle and the germinal center (GC)—are one such layer. Selective removal of Tfr cells in mice at the peak of an immune response results in a substantial increase of autoreactive antibodies, while low Tfr cell frequencies are negatively associated with human autoimmune diseases, further suggesting a key role in the regulation of B cell tolerance. Most previous work has studied Tfr cells at the peak of a GC reaction, meaning that their contributions at steady state and following cessation of a GC are unknown. Without knowledge of the entire life cycle of Tfr cells— including their initial development, phenotype differentiation, and maintenance outside of a GC—we will remain ignorant to additional roles that these cells likely play in maintaining immunity. Early adoptive transfer studies have suggested that the majority of Tfr cells derive from existing regulatory T cell (Treg) precursors. Alternatively, some lines of evidence controversially hint that a small subset of Tfr cells may also differentiate from Foxp3neg T helper cells of foreign antigen specificity, though such populations have not been consistently identifiable. Based on these data, we hypothesize that most Tfr-phenotype cells elicited during a GC reaction represent stable pre- existing thymus-derived Treg cells reactive to self-antigens. As proposed below, we will define the development, differentiation, and stability of Tfr cells. We will also assess the extent to which Tfr cells are reactive to foreign versus self-antigens. To accomplish these aims, we will generate T cell receptor retrogenic mice expressing monoclonal populations of Tfr biased clones of interest, allowing us to study naturally occurring Tfr cells at the clonal level. We will track the entire in vivo life cycle of individual Tfr biased clones, both at steady state and after cessation of a GC response, providing key insights into the biology of these cells. Finally, we will investigate the antigen specificity of Tfr cells by assessing their in vitro reactivity to dendritic cells or B cells loaded with self or foreign antigens. The findings obtained from this project will provide us with a clear model of the complete developmental trajectory and potential foreign reactivity of Tfr cells. This model will enable us to further study these cells in previously unappreciated contexts, thereby improving our understanding of how Tfr cells may succeed—or fail—to prevent autoimmunity.


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 = $50,114 )
2026	2026	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	2	1/9/2026	NON-COMPETING CONTINUATION	$49,538
2026	2026	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	002	2	4/10/2026	NON-COMPETING CONTINUATION	$576
2026	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	1	1/8/2026	NEW	$0
														Subtotal = $50,114

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	1	4/4/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	1	7/25/2024	NEW	$48,974
														Subtotal = $48,974

Grand Total All Awards = $99,088

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Development, stability, and antigen specificity of T follicular regulatory phenotype cells

Award Number: F31AI186394

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 11/01/2024

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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