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Peroxisomal control of CD4+ T cell inflammatory responses

Award Number: R21AI200165
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: 06/16/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Peroxisomal control of CD4+ T cell inflammatory responses - SUMMARY: Excessive proinflammatory activity of CD4+ T cells drives the pathogenesis of numerous inflammatory and autoimmune diseases. Intracellular organelles (IOs), in part via regulation of cellular metabolism, maintain homeostasis of the host immune responses. Among different IO-regulated metabolic pathways, fatty acid (FA) oxidation shapes immune cell function, systemic/tissue inflammation, and pathogenesis of various diseases. In this setting, the role of mitochondrial FA oxidation is best appreciated. However, whether other IOs, and specifically peroxisomes (which work closely with Mt) via metabolism of very long chain fatty acids (VLCFAs), dictate immune cell and specifically CD4+ T cell inflammatory functions and disease pathogenesis is largely unexplored. Thus, here we propose to examine how peroxisomes, via peroxisomal fatty acid β-oxidation (PFAbO), dictate CD4+ T cell transcriptome/metabolome/function and systemic/tissue inflammation. Of note, acyl-coenzyme A oxidase 1 (ACOX1) is the rate-limiting enzyme in the PFAbO pathway. Our novel data suggest that ACOX1 function has a robust impact on CD4+ T cell inflammation. We show that LOF mutation in Acox1 gene (Acox1Δ): (a) preferentially differentiates naïve CD4+ T cells to the Th17 cell subset, increases tissue Th17 cell pathogenic cytokine (IL-17) production, and promotes the existence of a Treg cell inflammatory phenotype; (b) leads to systemic hyperinflammation after challenge with T cell-specific stimuli. Mechanistically, we show that: (c) genetic ablation of adaptive immune cells in Acox1Δ mice (Rag1 KO/Acox1Δ mice) restricts liver inflammation and damage, while (d) inhibition of VLCFA accrual (bezafibrate-driven inhibition of Elovl1) in Acox1Δ CD4+ T cells restricts their inflammatory function and liver damage in Acox1Δ mice. These new findings highlight the significance of PFAβO and VLCFAs in T cell inflammation and consequent tissue damage and support the overarching hypothesis that PFAβO/ACOX1 axis is a key negative regulator of CD4+ T cell inflammatory and pathogenic functions. Our hypothesis will be tested via linked but independent high- risk/high-reward aims and the use of innovative approaches and novel mouse models. Specifically, we aim to define: (i) the role of PFAβO/ACOX1 axis on the inflammatory vigor of CD4+ T cell subsets and tissue (Aim 1); and (ii) the impact of VLCFA metabolism on PFAβO-Acox1 regulation of CD4+ T cell inflammatory vigor (Aim 2). Given the promise for therapeutic targeting of cellular metabolic pathways and unwanted inflammation, in addition to the demand of developing treatments for CD4+ T cell-associated inflammatory conditions and those associated with peroxisome dysfunction (e.g., metabolic syndrome, peroxisomal disorders), our work will provide critical, new knowledge towards understanding of how non-traditionally studied IOs shape immune responses and inflammatory disease pathogenesis – with the emphasis on peroxisome and PFAbO function in CD4+ T cells.


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 = $202,500 )
2026	2026	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Allergy and Infectious Diseases Research	000	1	6/16/2026	NEW	$202,500
														Subtotal = $202,500

Grand Total All Awards = $202,500

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Peroxisomal control of CD4+ T cell inflammatory responses

Award Number: R21AI200165

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: 06/16/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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