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Regulatory T cells maintain immune homeostasis through translation control

Award Number: R01AI181275
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: 12/13/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Regulatory T cells maintain immune homeostasis through translation control - PROJECT SUMMARY The immune system needs to distinguish between self and non-self, and between pathogen and commensal. In part it does through the function of regulatory T cells, a specialized subset of CD4 T cells that are critical for maintaining immune homeostasis, as well as maintaining tolerance toward self-antigens. Their importance to maintaining peripheral tolerance was illustrated from experiments of nature in both humans (IPEX syndrome) and mice (scurfy mutation) where loss of this subset of T cells results in the onset of fatal autoimmunity. Treg dysfunction has also been found to play a role in autoimmune diseases such as type 1 diabetes and multiple sclerosis. Tregs have the ability to potently suppress CD4 effector T cells (Teff) either directly or through the modulation of antigen presenting cells (mainly DCs) to ultimately suppress activation, proliferation, and subsequent effector functions of Teff cells. Several mechanisms have been proposed for Treg-mediated suppression, including release of suppressive cytokines and expression of inhibitory receptors. However, very little is known mechanistically as to the effect of suppression on Teff cell function. We found that Tregs promoted a significant drop in overall translational activity of CD4 Teff cells. Rather than inducing a global, non-specific translational shutdown in Teff cells, Tregs induced a specific remodeling of the translatome, with several mRNAs whose transcription was unaffected no longer present on ribosomes. These data provide novel insights into Treg function and identify new pathways that are potentially available for therapeutic intervention. The goal of the studies in this proposal are to determine the molecular mechanisms that underlie Treg-mediated translatome remodeling in Teffs, and to ask whether this mechanism is altered in human autoimmune disease. To achieve this we will: determine the role of RNA and RNA-binding proteins in Treg-mediated suppression of translation (Aim 1) and determine the role of translation control in human Treg function (Aim 2).


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 = $844,245 )
2026	2026	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Allergy and Infectious Diseases Research	000	3	11/29/2025	NON-COMPETING CONTINUATION	$844,245
														Subtotal = $844,245

Issue Date FY: 2025 ( Subtotal = $831,400 )
2025	2025	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Allergy and Infectious Diseases Research	000	2	10/24/2024	NON-COMPETING CONTINUATION	$831,400
														Subtotal = $831,400

Issue Date FY: 2024 ( Subtotal = $888,447 )
2024	2024	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Allergy and Infectious Diseases Research	001	1	12/15/2023	NEW	$0
2024	2024	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Allergy and Infectious Diseases Research	000	1	12/13/2023	NEW	$801,433
2024	2024	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Allergy and Infectious Diseases Research	002	1	9/3/2024	NEW	$87,014
														Subtotal = $888,447

Grand Total All Awards = $2,564,092

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Regulatory T cells maintain immune homeostasis through translation control

Award Number: R01AI181275

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: 12/13/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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