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Regulatory CD4+ T (Treg) cells dynamics in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD)

Award Number: R01DK146906
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Regulatory CD4+ T (Treg) cells dynamics in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) - PROJECT SUMMARY Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major global health issue. The lack of effective therapies for MASLD is attributed to limited knowledge of disease etiopathogenesis. The processes that regulate development of MASLD and its progression to MASH are complex and remain poorly understood. Activation of proinflammatory immune responses in the liver microenvironment is paradigmatically viewed as a critical causative link between obesity and MASLD pathogenesis. However, the function and role of immunoregulatory arms of the immune system in the liver microenvironment and their impact on MASLD pathogenesis remain underdeveloped and represent a key knowledge gap. Regulatory T cells (Treg cells) are considered a critical anti-inflammatory immune cell type, their homeostasis and function are regulated by diverse processes, including nutrient availability (e.g., fatty acids [FA]) and microenvironmental signals (e.g., cytokines). Inflammatory microenvironment can drive Treg cells adaptation to acquire characteristics typical of other CD4+ T cell subsets, such as Th1 or Th17, which enables them to target various inflammatory situations more effectively. However, under sustained inflammatory conditions, Treg cells may lose their suppressive function and turn pro- inflammatory, which orthodoxically can contribute to the severity of disease pathogenesis. However, whether and how the liver microenvironment during MASLD progression shapes putative hepatic Treg cell character and functions has not been studied. Our exciting preliminary data demonstrate that humans and mice with MASLD exhibit an increase in the number of hepatic FOXP3+ Treg cells that display an activated and inflammatory phenotype as defined by high expression of CD44, CXCR3, IL-17A, IFN, and TNF. Further, unique to the liver, our data demonstrate that: (i) the frequency of hepatic Treg cells positively correlates with MASLD progression, and (ii) mouse hepatic Treg cells display impaired suppressive capacity and acquire inflammatory capacities associated with Th1 or Th17 cells. Mechanistically, our data demonstrate that (iii) depletion of Treg cells in obese mice with MASLD improves hepatocellular damage, and (iv) genetic inhibition of peroxisomal fatty acid - oxidation (FAO) exacerbates hepatic Treg cells inflammatory functions. Thus, given our preliminary findings and published data in the literature, I propose the overarching hypothesis that hepatic Treg cells transition from suppressive to inflammatory character and function promotes MASLD progression. In this proposal, I aim to: 1) Determine the character and function of hepatic Treg cells during MASLD progression. 2) Determine the role of FAO in instructing hepatic Treg cell dysfunction in MASLD. The findings from the proposed application have the potential to discover new pathogenic mechanisms of disease progression that may be amenable therapeutic targets.


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 = $714,898 )
2026	2026	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/23/2026	NEW	$714,898
														Subtotal = $714,898

Grand Total All Awards = $714,898

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Regulatory CD4+ T (Treg) cells dynamics in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD)

Award Number: R01DK146906

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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