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Developmental acquisition of memory-phenotype CD8+ T cell function in infection and cancer

Award Number: F30AI183709
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Developmental acquisition of memory-phenotype CD8+ T cell function in infection and cancer - PROJECT SUMMARY/ABSTRACT In unprimed specific pathogen free and germ-free mice, there exists a population of αβ CD8+ T-cells that exhibit hallmarks of agonist ligand encounter, termed CD8 memory phenotype (CD8-MP) cells. These cells account for ~10% of the CD8+ T cell repertoire in adult mice, have a CD44hiCD122+ phenotype, display other memory markers shared by ‘true memory’ CD8+ T cells (CD8-TM) generated in response to pathogen challenge, and have incompletely defined functions. Previously, CD8-MP cells were thought to develop in the periphery due to subthreshold T-cell receptor (TCR) signaling to non-cognate self-antigen and in response to cytokine signaling. However, recent work from our lab demonstrated that CD8-MP differentiation is a robust and conserved TCR- instructed process driven by the recognition of agonist self-ligands in the thymus and consolidated in the periphery. Importantly, we also demonstrated that select CD8-MP-biased clones are recurrently enriched in oncogene-driven prostate tumors and express high densities of PD-1, suggesting a previously unappreciated role for CD8-MP cells in the immune response to cancer. The objective of this proposal is to define the immunological mechanisms driving the differentiation of CD8-MP cells and the functional potential imparted by this process by analyzing CD8-MP functional activity in settings of infection and cancer. We will test the hypothesis that the differentiation of CD8-MP cells is a two-step process, triggered by the recognition of self- pMHC-I antigen displayed by medullary thymic epithelial cells (mTECs), followed by sensing of MHC-I and IL- 15 in the periphery, which confer CD8-MP cells with a unique “non-cytolytic” functional profile. In Aim 1, we will define the antigen presenting cells and accessory signals directing the differentiation of CD8-MP cells at both a polyclonal and monoclonal level, utilizing our TCR “retrogenic” mouse pipeline and our previously identified naturally occurring CD8-MP biased clones. In Aim 2, we will identify CD8-naïve and CD8-MP-biased clones reactive to the same model antigen and utilize our TCRrg pipeline to interrogate the function of these cells following agonist ligand encounter in a tumor model and in other inflammatory contexts. Elucidating these mechanisms will provide needed insight into the biology of this prevalent T cell subset and will have key implications for our understanding of self-tolerance and cancer.


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 = $55,114 )
2026	2026	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	2	4/3/2026	NON-COMPETING CONTINUATION	$55,114
														Subtotal = $55,114

Issue Date FY: 2025 ( Subtotal = $54,538 )
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	1	2/25/2025	NEW	$53,974
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	1	7/31/2025	NEW	$564
														Subtotal = $54,538

Grand Total All Awards = $109,652

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Developmental acquisition of memory-phenotype CD8+ T cell function in infection and cancer

Award Number: F30AI183709

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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