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Beta-cell self-antigen recognition by diabetogenic CD8 T cells

Award Number: R01DK135968
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: 03/01/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Beta-cell self-antigen recognition by diabetogenic CD8 T cells - Project summary Type 1 diabetes (T1D) is a result of T-cell mediated destruction of insulin-producing beta-cells in the pancreatic islets. Autoreactive CD8 T cells are required in this “mistaken” immune response but how they drive disease is ill-defined. There are two key time points during the life of autoreactive T cells closely related to disease, namely, their creation in the thymus and activation in the periphery. The former fails to eliminate the potentially pathogenic T cells whereas the latter allows them to travel to and stay in the target tissue to mediate damage. Both events are strictly dependent on recognition of beta-cell self-antigens. However, little is known about how diabetogenic CD8 T cells recognize beta-cell antigens. We have over the years studied T cell antigen recognition using novel ultrasensitive two-dimensional (2D) force-based methods, showing 2D TCR affinity and bond lifetime with peptide:MHC as two main kinetics parameters that dictate thymocyte selection outcome and T cell effector functions. The current project aims to use these 2D methods to define binding kinetics of beta- cell antigen recognition by diabetogenic CD8 T cells in the context of their thymic development, peripheral effector function, and T1D pathogenesis. Our preliminary data show that CD8 T cells form weak bonds with beta-cell antigens during thymocyte selection but increase bond strength upon activation. Such change of self- reactivity is mediated by coreceptor CD8. In contrast, the same parameters did not change for foreign antigen recognition. These data support our central hypothesis that, in autoimmune diabetes, CD8 fundamentally alters self-antigen recognition through modulation of TCR binding kinetics, thereby endowing CD8 T cells with heightened self-reactivity that overcomes self-tolerance to mediate beta-cell destruction. We propose two specific aims to test this hypothesis. In Aim1, we will define 2D affinity and bond lifetime of beta-cell antigen recognition by CD8 T cells. We hypothesize that diabetogenic CD8 T cells, even at a single clonal level, are highly adaptive in antigen recognition such that they use weak binding kinetics to survive central and peripheral tolerance but greatly increase self-reactivity to precipitate disease. We will use a panel of monoclonal diabetogenic TCR cell clones based on the NOD mouse model of T1D to systemically characterize beta-cell antigen recognition during diabetogenic CD8 T cell thymocyte selection and peripheral activation and investigate a causal relationship between plasticity of beta-cell antigen recognition and autoimmune diabetes. In Aim2, we will elucidate the underlying mechanisms of beta-cell antigen recognition. We hypothesize that plasticity of beta-cell antigen recognition by diabetogenic CD8 T cells is due to CD8 binding kinetics with MHC. We will first define the role of CD8 in the overall beta-cell antigen recognition. We will then test a sub- hypothesis that unique patterns of CD8 glycosylation determine adaptability of CD8 binding kinetics by T cell glycan profiling, phenotyping, and single cell transcriptomic analysis.


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: 2025 ( Subtotal = $385,000 )
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	6/12/2025	NON-COMPETING CONTINUATION	$38,500
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/21/2025	NON-COMPETING CONTINUATION	$346,500
														Subtotal = $385,000

Issue Date FY: 2024 ( Subtotal = $369,600 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/26/2024	NON-COMPETING CONTINUATION	$346,500
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/6/2024	NON-COMPETING CONTINUATION	$23,100
														Subtotal = $369,600

Issue Date FY: 2023 ( Subtotal = $384,583 )
2023	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	3/9/2023	NEW	$0
2023	2023	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/27/2023	NEW	$384,583
														Subtotal = $384,583

Grand Total All Awards = $1,139,183

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Beta-cell self-antigen recognition by diabetogenic CD8 T cells

Award Number: R01DK135968

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: 03/01/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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