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Suppression of T-bet+ B cells in lupus by tryptophan metabolites

Award Number: R21AI190764
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: 02/09/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Suppression of T-bet+ B cells in lupus by tryptophan metabolites - PROJECT SUMMARY This proposal aims to (i) identify immunoregulatory metabolic signals induced by IL-4 that suppress TLR7 stimulation of lupus pathogenic B cells including T-bet+ B cells, and (ii) develop safer SLE therapeutics using immune-regulatory metabolites to inhibit TLR7-induced lupus pathogenic B cell development. Our recent findings show that in SLE, reduced IL-4R expression and defective maintenance of naïve B cells contribute to increased T-bet+CD11c+ B cells and autoantibody development. Co-culture with IL-4 blocked interferon- promoted development of T-bet+CD11c+ B cells and preserved a T-bet−CD11c− phenotype. IL-4 treatment in vivo suppressed a TLR7 ligand R848-promoted development of T-bet+ age-related B cells (ABCs), germinal center (GC) dark zone B cells, CD138+ plasma B cells (PBs), and autoantibody in BXD2 mice. Preliminary data from lupus BXD2 mouse B cells treated with IL-4 revealed upregulation of IL4i1, which generates indole- 3-pyruvic acid (IPyA) from tryptophan (Trp), and metabolites including kynurenine (Kyn) that activate the aryl hydrocarbon receptor (AhR) pathway. In the absence of IL-4, AhR agonists including Kyn and 6- Formylindolo[3,2-b]carbazole (FICZ) suppressed T-bet+CD11c+ B cell development and preserved naïve B cells. A deficiency of AhR in B cells enhanced TLR7 ligand-induced T-bet+ B cell development in vivo and nullified FICZ suppression of T-bet+ B cells in vitro. We hypothesize that IL-4 stimulates IL4i1-mediated IPyA and Kyn to inhibit ABC, GC, and PB development via AhR activation. Aim 1 will determine the Trp metabolic signals induced by IL-4 to inhibit TLR7-induced lupus autoantibody precursor B cells including ABCs and GC B cells in vivo. The induction and essential role of B-cell endogenous IL4i1, Ido1, and AhR for IL-4 suppression of lupus pathogenic B cell development will be determined in wild-type (Aim 1A) and knock-out mice (Aim 1B). Aim 2 will determine what IL-4-induced Trp metabolites can effectively suppress TLR7-mediated ABCs and GC B cell development in vivo. The primary metabolites that activate the AhR program and can be induced by IL-4 in vivo in B cells will be determined (Aim 2A). Whether these metabolites can suppress TLR7-induced development of ABCs, GC B cells, and autoantibodies will be determined (Aim 2B). Significance: This research shifts focus from pro-inflammatory factors to strategies that restore immune cell homeostasis, potentially offering safer SLE treatments. Innovation: The proposed project aims to discover metabolites that regulate B-cell homeostasis, offering novel, druggable targets for SLE therapy. Team and Environment: Dr. Mountz specializes in cytokine-mediated B-cell transcriptomics in SLE, while Dr. Barnes, Director of UAB's TMPL, will provide metabolomics expertise. Dr. Corinne Augelli-Szafran who specializes in small molecule drug discovery will be a collaborator to assist in developing the hit-to-candidate pipeline of Trp metabolite prioritization and screening.


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 = $409,750 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	1	2/9/2026	NEW	$409,750
														Subtotal = $409,750

Grand Total All Awards = $409,750

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Suppression of T-bet+ B cells in lupus by tryptophan metabolites

Award Number: R21AI190764

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: 02/09/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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