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Interrogating selection of autoreactive T cells using isogenic human thymic organoids

Award Number: K99DK146108
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Interrogating selection of autoreactive T cells using isogenic human thymic organoids - PROJECT SUMMARY Type 1 diabetes (T1D) is an autoimmune disease that results in the destruction of insulin-producing pancreatic β-cells, rendering the T1D patient dependent on a continuous supply of exogenous insulin. Insulin therapy is a common treatment but does not provide a cure. Indeed, insulin injections and insulin pumps can successfully extend life expectancy, but persistent fluctuations in glucose levels can result in life-threatening complications including episodes of hypoglycemia, cardiovascular disease, neuropathy, and renal failure. Many attempts to circumvent the autoimmune response underlying T1D have utilized broad, non-specific immune suppression, which can temporarily slow the progression of disease in newly diagnosed individuals, but none have demonstrated clinical remission or even any overt effect on disease course long term. The establishment of immune self-tolerance requires the synergy of two different systems, central tolerance in the thymus and peripheral tolerance in the tissues, that work in concert to prevent autoimmunity. Deficiencies in peripheral tolerance are more widely studied and have been correlated with human autoimmune disorders including T1D. Yet, attempts to renew self-tolerance mechanisms in the periphery have displayed only modest, if any, impact on disease progression. These data suggest that overcoming the initial breakdown in central tolerance is key to preventing autoimmunity. However, the mechanisms governing central tolerance that contribute to or influence T1D onset are still largely unknown, foremost due to the absence of human systems that can be used to interrogate selection processes in a matched manner. The development of protocols in our lab as well as others to induce the in vitro differentiation of human pluripotent stem cell (hPSC)-derived thymic cells (sTC) followed by in vitro culture of human thymic organoids or transplantation of sTC into thymus-deficient mice have opened the door for innovative approaches to answering these pressing questions. In this proposal, I hypothesize low affinity TCR autoreactive T cells will escape the selection process, ultimately allowing for β-cell-reactive T cells to persist, while high affinity TCRs will be removed or diverted to the Treg fate. To test this hypothesis, the following independent but interrelated aims using human isogenic systems will be performed: (1) determine how autoreactive TCR affinity influences human thymic T cell selection, and (2) evaluate the functional consequences of autoreactive TCR affinity on β-cell reactivity. Collectively, genetic engineering of stem cell-derived thymic cells and T cell progenitors to develop isogenic thymic organoids or novel in vivo humanized systems will provide key insights into cellular tolerance mechanisms in human T1D, addressing a critical need in the T1D field. Completion of these studies may also illuminate novel targets for T1D intervention or treatment, allowing us to understand and generate patient-derived polyclonal thymus educated regulatory T cell pools or diverse T cell repertoires.


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 = $90,000 )
2026	2026	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/31/2026	NEW	$90,000
														Subtotal = $90,000

Grand Total All Awards = $90,000

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Interrogating selection of autoreactive T cells using isogenic human thymic organoids

Award Number: K99DK146108

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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