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Signaling and Selection in Germinal Center B cells

Award Number: R01AI105018
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: 03/15/2014
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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Signaling and Selection in Germinal Center B cells - The germinal center (GC) response generates long-lived, high affinity humoral immunity. GC B cells (GCBC) undergo affinity-based positive selection and can differentiate into either memory B cells (MBC) or long-lived plasma cells (LLPC). To enact positive selection and differentiation, a subset of GCBC that receive requisite external signals must modify their transcription factor (TF) networks to guide cells into very different fates. How does the simultaneous processes of positive selection and commitment to differentiation occur? What signals elicit each fate and how do GCBC respond to those signals at the cellular, molecular and epigenetic levels? These are pivotal problems that have been very challenging to address. In this proposal we will use novel approaches and reagents to ask how different signals and downstream pathways interact to determine GCBC fate. We will determine the molecular and epigenetic basis for cell differentiation choices within the GC and create a new map of the TF-driven gene regulatory networks that underlie cell fate choices in the GC. We will do this by directly studying authentic GCBC, as our work has shown that in vitro-generated or naïve B cells have very different transcriptomes and epigenomes from GCBC; further, the major signaling pathways downstream of BCR, CD40 and IL-21 are all reprogrammed specifically in GCBC. Recently, we discovered how combinations of BCR and T cell-derived signals induce expression of cMyc and GC positive selection, as well as promote PC and MBC precursor differentiation. We identified the differential modulation of key TFs—BLIMP1, BCL6, and IRF4—in response to BCR vs IL-21 signals, when delivered with CD40 signals, with the latter favoring PC differentiation. Signals that govern GCs may shift with time, and our prior work showed that early GCs generate MBC but late GCs mainly emit PCs; the mechanisms behind this remain unknown. The identification of GCBC that have altered their TF expression pattern in response to defined stimulus combinations suggests that these cells are in the process of committing to differentiation. In Aim 1 we will test whether shifts in GC output are B cell-intrinsic or extrinsic, whether IL-21 vs BCR signals selectively promote PC development vs MBC development and, using novel fluorescent protein TF reporter mice that enable us to isolate live cells that are responding, generate a complete transcriptomic and epigenetic profile of GCBC undergoing differentiation. In Aim 2 we will determine how signals promote positive selection at both the functional and gene expression/epigenetic level. In Aim 3 we will determine the function of three TFs whose functional roles in GCBC are unexplored (TOX, TOX2, and LITAF), as well as conduct a CRISPR screen to detect TFs important in GCBC differentiation and expansion. These experiments are at the conceptual and technical forefront of B cell biology. As the GC is central to long-lived natural immunity, vaccine immunity, autoimmunity and even tumor immunity, it is of great significance and importance to have a deeper and more mechanistic understanding of how it operates. Thus, this work—though fundamental in nature—has broad scientific and biomedical impact.


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 = $549,892 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	11	2/19/2026	COMPETING CONTINUATION	$549,892
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	001	11	3/13/2026	COMPETING CONTINUATION	$0
														Subtotal = $549,892

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	10	6/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $465,084 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	001	10	5/24/2024	NON-COMPETING CONTINUATION	$46,507
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	10	2/12/2024	NON-COMPETING CONTINUATION	$418,577
														Subtotal = $465,084

Issue Date FY: 2023 ( Subtotal = $465,427 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	9	3/16/2023	NON-COMPETING CONTINUATION	$465,427
														Subtotal = $465,427

Issue Date FY: 2022 ( Subtotal = $463,447 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	8	2/25/2022	NON-COMPETING CONTINUATION	$463,447
														Subtotal = $463,447

Issue Date FY: 2021 ( Subtotal = $458,535 )
2021	2021	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	001	7	2/16/2021	NON-COMPETING CONTINUATION	$458,535
2021	2018	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	5	12/11/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $458,535

Issue Date FY: 2020 ( Subtotal = $457,682 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	001	6	7/8/2020	COMPETING CONTINUATION	$0
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	6	2/27/2020	COMPETING CONTINUATION	$457,682
														Subtotal = $457,682

Issue Date FY: 2018 ( Subtotal = $380,950 )
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	5	3/2/2018	NON-COMPETING CONTINUATION	$380,950
														Subtotal = $380,950

Issue Date FY: 2017 ( Subtotal = $380,950 )
2017	2017	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	4	2/21/2017	NON-COMPETING CONTINUATION	$380,950
														Subtotal = $380,950

Issue Date FY: 2016 ( Subtotal = $380,950 )
2016	2016	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	3	2/15/2016	NON-COMPETING CONTINUATION	$380,950
														Subtotal = $380,950

Issue Date FY: 2015 ( Subtotal = $380,950 )
2015	2015	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	2/19/2015	NON-COMPETING CONTINUATION	$380,950
														Subtotal = $380,950

Issue Date FY: 2014 ( Subtotal = $379,737 )
2014	2014	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	3/13/2014	NEW	$379,737
2014	2014	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	001	1	9/16/2014	NEW	$0
														Subtotal = $379,737

Grand Total All Awards = $4,763,604

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Signaling and Selection in Germinal Center B cells

Award Number: R01AI105018

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: 03/15/2014

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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