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

Function of Paired Activating and Inhibitory FcR Signaling in Immune Regulation

Award Number: F31AI200253
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 11/01/2026
PERIOD OF PERFORMANCE END DATE: 10/31/2029

Group Awards By:

View Award Description

Function of Paired Activating and Inhibitory FcR Signaling in Immune Regulation - PROJECT SUMMARY Recognition of secreted IgG by Fc Receptors (FcRs) on innate immune cells is critical for clearing pathogens by phagocytosis. However, overactive FcR signaling can damage healthy tissue. Macrophages, an innate immune cell type, regulate tissue homeostasis and pathogen clearance through immune effector functions including cytokine release, antibody-dependent cellular toxicity, antigen presentation, and phagocytosis. Macrophages express five ITAM-bearing activating FcRs, and a single ITIM-bearing inhibitory FcR: FcγRIIB. Misregulated FcγRIIB signaling is associated with chronic autoimmune conditions. From a systems-perspective, FcγRIIB is puzzling. If macrophages can simply downregulate activating FcR, why does FcγRIIB exist? Given that FcγRIIB uniquely shares the ligand of IgG with its cognate activating FcγRs, the dissection of its specific effects from the activating FcRs is particularly challenging. To solve this, we designed a synthetic receptor system that allows selective stimulation of Fc𝛾RIIB and activating Fc𝛾Rs independently using DNA nanotechnology. Using this system, our preliminary data demonstrates that FcγRIIB stimulation does not inhibit a specific stage of phagocytosis but rather sets a time limit on the duration of the phagocytic attempt, thereby increasing the frequency of phagocytic failures. We confirmed that this effect required with recruitment of SHIP1, an inositol phosphatase known to complex with FcγRIIB’s ITIM and dephosphorylate PI(3,4,5)P3 (PIP3), a key signaling lipid required for phagocytosis. Further, a computational model of phospholipid conversion during concurrent activating and inhibitory FcR signaling generates an incoherent feedforward loop that supports our in vivo observations. Therefore, the central hypothesis of this proposal is that FcγRIIB inhibits phagocytosis by enacting a phospholipid mediated time-limit on phagocytosis. To test this hypothesis, I will utilize genetically altered macrophages with FcγRIIB knocked out or overexpressed. In Aim 1, I will test the hypothesis that the dramatically inhibited FcγRIIB phenotype is a result of decreased phagocytosis attempt durations through high resolution quantitative imaging analysis of timelapses capturing phagocytosis. In Aim 2, I will demonstrate that differences in phagocytic attempt duration in macrophages with and without FcγRIIB signaling are mediated by changes to PIP3 dynamics at the progressing phagocytic cup. I will accomplish this with the use of a highly specific fluorescent PIP3 probe. Finally, Aim 3 will provide insight into this inhibitory mechanism’s role in controlling macrophage behavior in response to various IgG isotypes during different inflammatory contexts, by measuring both phagocytic timing and PIP3 dynamics during engulfment of targets opsonized with different IgG isotypes. Collectively, this work will establish FcγRIIB as a PIP3-driven molecular timer that enforces strict time limits on phagocytic persistence, resolving how its dysregulation causes pathogenic outcomes and providing mechanistic criteria to optimize therapeutic antibody isotype selection for tuning effector cell engagement.


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 = $48,764 )
2026	2026	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Allergy and Infectious Diseases Research	001	1	5/8/2026	NEW	$0
2026	2026	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Allergy and Infectious Diseases Research	000	1	5/8/2026	NEW	$48,764
														Subtotal = $48,764

Grand Total All Awards = $48,764

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Function of Paired Activating and Inhibitory FcR Signaling in Immune Regulation

Award Number: F31AI200253

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 11/01/2026

PERIOD OF PERFORMANCE END DATE: 10/31/2029

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer