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Systematic Mapping of Microbiota and Dietary Determinants of CD4 T Cell Fate

Award Number: K99AI201798
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/03/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Systematic Mapping of Microbiota and Dietary Determinants of CD4 T Cell Fate - PROJECT SUMMARY/ABSTRACT CD4+ T cells coordinate intestinal homeostasis by recognizing microbiota, food, and pathogens via their T cell receptors (TCRs) and differentiating into antigen-specific effector (e.g. Th17, Th1, Tfh) or regulatory (Treg) lineages. Dysregulated CD4+ T cell responses are implicated in the pathogenesis of inflammatory bowel diseases, food allergy, and infectious diseases, yet we lack a fundamental understanding of their antigen specificity and how this relates to cell fate during homeostasis and disease. The prevailing paradigm suggests that distinct microbial taxa preferentially induce the differentiation of particular CD4+ T cell lineages (e.g. segmented filamentous bacteria and Th17, Helicobacter hepaticus and Treg). However, many widely studied organisms exhibit atypical physiology, and foundational studies often used reductionist approaches such as monocolonized gnotobiotic mice and model TCR-antigen pairs that fail to capture the complexity of a natural microbiome and diet and the diversity of the native TCR repertoire. To overcome these limitations, I developed a gnotobiotic mouse model naturally colonized from birth with a 116-strain human microbiota and paired it with a novel high-throughput platform to clone and characterize native TCR specificity at single-cell resolution. Preliminary results reveal a striking pattern: microbiota- and diet-reactive TCRs are overwhelmingly enriched in the induced Treg lineage, while effectors show little reactivity. These findings challenge the prevailing paradigm and support a revised model wherein Treg induction is the default outcome of foreign antigen recognition in the healthy gut. Aim 1 will systematically define the specificity of ~1000 TCRs from all major intestinal CD4+ T cell populations to formally test the prevailing “species specific effector” paradigm versus the “Treg as default” framework. Aim 2 will assess how CD4+ T cell phenotype and specificity shift in acute and chronic inflammation, revealing mechanisms by which tolerance is maintained and ultimately broken in disease. Together, these studies will define a mechanistic framework for understanding CD4+ T cell fate decisions in the healthy gut and their dysregulation in chronic disease. They will also provide a large atlas of TCR-antigen pairs and a broadly applicable platform for characterizing TCR specificity at high-throughput in complex antigenic environments. This research will be complemented by formal training in anaerobic microbiology and microbial and single-cell genomics, under the guidance of an interdisciplinary team including my primary mentor Dr. Michael Fischbach and advisory committee members Drs. Daniel Mucida, Gabriel Victora, and Ansuman Satpathy. Together, these efforts will launch my independent research program as a physician-scientist with a focus on the principles that govern tolerance, immunity, and disease in the gut.


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 = $166,425 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	1	8/3/2026	NEW	$166,425
														Subtotal = $166,425

Grand Total All Awards = $166,425

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Systematic Mapping of Microbiota and Dietary Determinants of CD4 T Cell Fate

Award Number: K99AI201798

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/03/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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