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HCMV-induced innate-like CD8 T cells and allogeneic HCT outcome

Award Number: R01AI150999
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: 04/09/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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HCMV-induced innate-like CD8 T cells and allogeneic HCT outcome - PROJECT SUMMARY Human cytomegalovirus (HCMV) infects all populations with a penetrance of 50-100% and is kept latent by innate and adaptive surveillance. However, it is a significant cause of morbidity and mortality in conditions of immune reconstitution and suppression, such as in neonates and recipients of solid organ or hematopoietic cell transplants. The T cell response to HCMV through classical HCMV peptide-specific αβ cytotoxic T lymphocytes has been well-studied, and the development of NKG2C+ natural killer cells in response to HCMV infection and reactivation is under active investigation. In addition to these lymphocytes, however, large populations of αβ- TCR CD8 T cells that express NKG2C and other NK-associated receptors have also been observed in HCMV- seropositive healthy donors and patients. These innate-like NKG2C+ CD8 T cells appear to have broad activity against AML and HCMV-infected cells, no activity against uninfected allogeneic fibroblasts, and reduced expression of PD-1 in response to CD3 stimulation. RNAseq analysis has revealed that NKG2C+ CD8 T cells have reduced expression of the transcription factor Bcl11b, critical for cutting off alternative innate fates during the early thymic development of T cells. The central hypothesis of this proposal is that HCMV exposure induces an NKG2C+ CD8 T cell population by diverting clonotypic T cells toward an innate fate through the downregulation of Bcl11b, which alters TCR signaling and promotes alternative recognition pathways beneficial to leukemia patients. The first aim of the proposal is to evaluate the T cell identity of members of the NKG2C+ CD8 T cell population (clonality, TCR specificity and signaling) and how their transcriptional and epigenetic programs are altered from other CD8 T cells by Bcl11b loss. The second aim will assess the function of the NK- associated activating and inhibitory receptors on the NKG2C+ CD8 T cells, with the goal of identifying the mechanism behind their anti-tumor and anti-HCMV activity. Finally, in a collaboration with the Center for International Blood and Marrow Transplantation, an extensive hematopoietic cell transplantation patient sample bank and clinical database will be utilized to determine whether the post-transplantation emergence of an NKG2C+ CD8 T cell population impacts the risk of leukemia relapse and overall survival. Together, the results of these studies will elucidate not only the therapeutic potentials of this innate-like T cell population but also how adaptive and innate fates can be bridged.


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 = $688,546 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	5	2/25/2025	NON-COMPETING CONTINUATION	$688,546
														Subtotal = $688,546

Issue Date FY: 2024 ( Subtotal = $709,841 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	4	3/8/2024	NON-COMPETING CONTINUATION	$638,857
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	4	5/23/2024	NON-COMPETING CONTINUATION	$70,984
														Subtotal = $709,841

Issue Date FY: 2023 ( Subtotal = $733,090 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	3/6/2023	NON-COMPETING CONTINUATION	$733,090
														Subtotal = $733,090

Issue Date FY: 2022 ( Subtotal = $709,841 )
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	3/11/2022	NON-COMPETING CONTINUATION	$709,841
														Subtotal = $709,841

Issue Date FY: 2021 ( Subtotal = $759,700 )
2021	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	4/9/2021	NEW	$759,700
														Subtotal = $759,700

Grand Total All Awards = $3,601,018

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HCMV-induced innate-like CD8 T cells and allogeneic HCT outcome

Award Number: R01AI150999

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: 04/09/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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