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Integrating novel cellular and molecular technologies to advance deep profiling of T cells

Award Number: R01AI199138
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: 07/20/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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Integrating novel cellular and molecular technologies to advance deep profiling of T cells - The goal of this proposal is to develop innovative methodologies that enable profiling of CD4+ T cells and their responses at a breadth and depth that is currently out of reach. This will be achieved by integrating a novel cellular based technology we developed, called Coupling Assay for T cell Specificity (CATS), with cutting-edge molecular techniques. We think it is important to innovate in this space because CD4+ T cells sit at the apex of adaptive immunity, serving helper and regulatory roles that influence the responses of innate immune cells as well as B cells and other T cells. They therefore play an outsized role in regulating the healthy and diseased states that occur over the lifespan. Our rationale, supported by several major advances in immunotherapy that arose from fundamental insights into T cell biology, is simple – the more we know, the better equipped we are to develop new therapies that favor health over disease over the lifespan. In this proposal we will address a key challenge facing the field, which is that it remains difficult to detect and profile CD4+ T cells specific for microbial, tumor, or self-antigens because only a fraction of those that are specific for a given antigen (perhaps as low as 25%) can be detected by conventional means. Such poor detection is due to the low affinity of their T cell receptors (TCRs) for their cognate antigens. Our preliminary data establishes that CATS can identify T cell clonotypes with TCR affinities that are below the limit of detection of conventional approaches and can be combined with TCRseq to broadly profile the clonotypes that respond to antigen challenge. As is conventional for engineering/technology-development proposals, Aim 1 will use model mouse systems to establish and refine CATS-based methodologies designed to enumerate and study the signaling potential within a polyclonal response, profile the clonotypes specific for antigens, and tie those clonotypes to cell fate decisions. We will also establish methodologies to discriminate high (<200µM) vs low (>200µM) affinity T cells. Aims 2 and 3 will then perform proof-of-principle experiments to test these methodologies under more real-world conditions that are less well controlled. Aim 2 will use CATS-based methodologies to explore the rules governing TCR specificity to peptide antigens versus restriction to the MHCII molecules presenting the antigens. Aim 3 will then perform CATS-based deep profiling to explore age-associated changes in CD4+ T cell responses to pathogenic infection. The work proposed here will generate publications describing methodologies that will allow the field to better interrogate, and therefore understand, T cell biology. It will also provide novel insights into the rules governing antigen recognition, and how T cell responses change with aging.


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 = $3,195,716 )
2026	2026	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Allergy and Infectious Diseases Research	000	1	7/20/2026	NEW	$3,195,716
														Subtotal = $3,195,716

Grand Total All Awards = $3,195,716

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Integrating novel cellular and molecular technologies to advance deep profiling of T cells

Award Number: R01AI199138

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: 07/20/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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