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Exploring undefined roles of Calcineurin in restriction of autophagy-mediated TCF-1 degradation in CD8+ T cells

Award Number: R21AI191015
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: 02/04/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Exploring undefined roles of Calcineurin in restriction of autophagy-mediated TCF-1 degradation in CD8+ T cells - Project Summary Cytotoxic CD8+ T cells confer adaptive immune protection against viruses, intracellular pathogens, and cancer. Efficient CD8+ T cell immunity depends on regulation of a specific set of transcription factors as well as global cellular activity, including nutrient metabolism. We have found in our preliminary study that the activity of the TCR-induced phosphatase Calcineurin is essential for protection of the transcription factor TCF-1, which is critical for immunological memory, and for reprogramming amino acid metabolism for increase biogenesis in highly proliferative T cells through suppression of the catabolic process known as autophagy. Despite the importance of TCF-1 in immunological memory and durable T cell response and the demand for metabolic reprogramming, regulatory mechanisms by which T cells respond to antigens and inflammation and establish highly controlled states are not largely unknown. We initially found that inhibition of Calcineurin by the immunosuppressant Cyclosporin A promotes TCF-1 degradation through autophagy, and our additional experiments have suggested that Calcineurin is the central player that globally restricts the engagement of autophagy in activated T cells exposed to inflammatory cues, which not only leads to protection of TCF-1 but also governs amino acid and protein metabolism during T cell immune responses. In this proposed study, we will conduct multi-angled mechanistic analyses of the actions of Calcineurin in cytotoxic T cells to define the unexplored roles of this phosphatase. Given that Cyclosporin A and its related drug, FK-506, have been broadly used as immunosuppressants in patients undergoing organ transplantation and treatment of autoimmunity, expected findings from this study will provide new insights into T cell biology and into altered immunity in patients with pharmacological immune suppression.


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 = $427,625 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	1	2/4/2026	NEW	$427,625
														Subtotal = $427,625

Grand Total All Awards = $427,625

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Exploring undefined roles of Calcineurin in restriction of autophagy-mediated TCF-1 degradation in CD8+ T cells

Award Number: R21AI191015

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: 02/04/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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