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Investigating the development and regulation of the extrafollicular B cell response as a programmed response type

Award Number: R01AI192598
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: 07/16/2025
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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Investigating the development and regulation of the extrafollicular B cell response as a programmed response type - Abstract This is a proposal to advance our basic understanding of a critical but understudied aspect of immunity—the extrafollicular (EF) response. Upon activation, B cells enter either the EF response, or the germinal center (GC) response. The GC gives rise to high affinity memory B cells and long-lived plasma cells (PC), crucial elements of vaccine responses. While the GC is highly studied, the role of the EF response and how it is generated is much less well understood. Yet, the biology of the EF response is likely to be highly relevant to human health: Recent studies highlight the importance of the EF response, both in controlling infection and in dysregulated contexts such as Lupus and severe COVID infection. We have recently identified IL-12 as an upstream cytokine switch that directs B cells toward the EF response and suppresses GCs. In B cells, IL-12 induces autocrine feed-forward signaling between IL-12 and IFNg, resulting in distinct transcriptional changes and enhanced PC differentiation. B cells secrete IL-12, which promotes both their own differentiation and surprisingly, early TH1 differentiation. IL-12/IFNg signaling also induced the expression of CXCR3 by B cells, known to facilitate DC:T cell interactions during TH1 responses. DCs have also been shown to enhance PC differentiation in some contexts. EF foci form in locations rich in DCs and T cells, but the significance of this location is unknown. These findings lead to our central hypothesis - that the EF response is a specialized “response type” preferentially supporting rapid expansion and PC differentiation, and that EF foci are a niche with local cell-cell interactions and cytokine production, coordinated by inflammation-induced chemokines. GC B cells facilitate the differentiation of TFH, and though naïve B cells can invade existing GC, the bulk of the GC population is maintained through proliferation with infrequent differentiation. In Aim 1, we will test the role of B cells in enhancing the EF response locally, and test the self-renewal capacity of the undifferentiated “EF B cell” population. In Aim 2, we will isolate the continually proliferating EF B cell population and begin to characterize the EF B cell state transcriptionally and epigenetically. We will examine the effects of IL-12 and IFNg on this gene regulatory network. We will also target transcription factors that are predicted to regulate the EF B cell program and test these findings using human B cells. In Aim 3, we will characterize the EF foci as a niche, much like the GC is thought of, using spatial transcriptomics and genetic approaches to define the roles of DCs, CD4 T cells, and CXCR3 in the EF response. Collectively these studies will provide a significant conceptual advance for our understanding of the EF B cell response and enable the creation of new tools to study EF B cells and their progeny. This is an area of great need as relatively little is known about how the EF response is regulated. These studies are therefore poised to have a significant impact in advancing our understanding of the EF response, with a long-term objective of learning how to both restrain EF responses to treat EF-driven autoimmunity, and exploit the EF response for novel vaccine designs and cancer therapeutics.


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 = $570,476 )
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	2	5/26/2026	NON-COMPETING CONTINUATION	$570,476
														Subtotal = $570,476

Issue Date FY: 2025 ( Subtotal = $556,843 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	7/16/2025	NEW	$556,843
														Subtotal = $556,843

Grand Total All Awards = $1,127,319

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Investigating the development and regulation of the extrafollicular B cell response as a programmed response type

Award Number: R01AI192598

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: 07/16/2025

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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