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Defining mechanisms of CD8 T cell exhaustion in T1D

Award Number: R01AI141952
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: 04/10/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Defining mechanisms of CD8 T cell exhaustion in T1D - PROJECT SUMMARY/ABSTRACT A critical barrier to treating Type 1 Diabetes (T1D), an autoimmune disease in which the islet beta cells are destroyed by immune cells, is understanding the heterogeneity of disease. One source of immune heterogeneity recently identified across recent onset T1D subjects is the presence of partially exhausted CD8 T cells in subjects with beneficial response to anti-CD3 therapy (Long, et.al Science Immunology). Likewise, subjects with slower disease progression have great frequencies of islet-specific CD8 T cells with more features of exhaustion. Yet, the mechanisms underlying exhaustion in T1D are not well understood. By contrast, in chronic viral settings it is well established that the IL-2/IL-15 axis is involved in differentiation and persistence and CD8 exhaustion: increased IL-2 availability prevents differentiation, while response to IL-2/IL- 15 is required for persistence. In T1D, we published seminal studies along with others that link alterations in the IL-2/IL-15 axis with T1D. Here, we find that T1D subjects with lower frequencies of exhausted CD8 T cells have higher levels of CD4 IL-2 production and lower levels of IL-15 response in CD8 exhausted cells. Thus, IL- 2/IL-15 defects associated with T1D present a unique opportunity to elucidate the role of IL-2 on CD8 exhaustion. We hypothesize that alterations in the IL-2/IL-15 axis in T1D lead to decreased differentiation into islet-specific exhausted CD8 T cells and reduced persistence. We will test this hypothesis in two focused aims using samples from well curated human cohorts of established T1D, pre- clinical T1D and healthy control (HC) subjects, and multi-dimensional single cell approaches including mass cytometry (CyTOF), RNA-seq and ATAC-seq combined with innovative systems immunology approaches. In Aim 1, we propose to elucidate mechanisms of increased CD4 IL2 production that lead to reduced exhaustion at different stages of disease. In Aim 2, we will elucidate mechanisms of reduced IL-12/IL-15 response in exhausted CD8 T cells that results in limited persistence of exhaustion. Successful completion of these aims will 1) advance our understanding of CD8 T cell exhaustion as an understudied form of tolerance in T1D, 2) improve our understanding of immune factors contributing to T1D disease progression, and 3) provide the foundation for the development of therapies designed to promote exhaustion.


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: 2024 ( Subtotal = $578,210 )
2024	2024	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Allergy and Infectious Diseases Research	000	5	3/27/2024	NON-COMPETING CONTINUATION	$578,210
														Subtotal = $578,210

Issue Date FY: 2023 ( Subtotal = $574,380 )
2023	2023	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Allergy and Infectious Diseases Research	000	4	2/28/2023	NON-COMPETING CONTINUATION	$574,380
														Subtotal = $574,380

Issue Date FY: 2022 ( Subtotal = $559,756 )
2022	2022	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Allergy and Infectious Diseases Research	000	3	4/5/2022	NON-COMPETING CONTINUATION	$559,756
														Subtotal = $559,756

Issue Date FY: 2021 ( Subtotal = $544,224 )
2021	2021	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Allergy and Infectious Diseases Research	000	2	3/15/2021	NON-COMPETING CONTINUATION	$544,224
														Subtotal = $544,224

Issue Date FY: 2020 ( Subtotal = $544,224 )
2020	2020	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Allergy and Infectious Diseases Research	000	1	4/9/2020	NEW	$544,224
														Subtotal = $544,224

Grand Total All Awards = $2,800,794

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Defining mechanisms of CD8 T cell exhaustion in T1D

Award Number: R01AI141952

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: 04/10/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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