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Investigating the role of T1D candidate locus BACH2 in the regulation of peripheral tolerance mechanisms in T1D

Award Number: K99AI202086
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Investigating the role of T1D candidate locus BACH2 in the regulation of peripheral tolerance mechanisms in T1D - Genetic studies have implicated >150 genome wide loci conferring risk for type 1 diabetes (T1D) development, with notable enrichments in immune-related genes. Despite the identification of candidate genes, there remain considerable knowledge gaps regarding the impact of T1D risk loci on immune cell phenotype and function. Of note, the candidate gene BACH2 is a transcription factor containing a single nucleotide polymorphism (SNP) conferring risk for T1D (rs729298038G>A; OR=1.18; MAF=0.18). The risk variant has been linked to reduced enhancer accessibility and expression of BACH2 in naïve human T cells, while naïve CD8+ T cells derived from a mouse model with an orthologous mutation displayed reduced features of stemness and enhanced effector phenotype. BACH2 has been described as a guardian transcription factor in T cells, and a key regulator of stemness and exhausted phenotypes in the context of viral infection, cancer immunotherapy and autoimmunity. These phenotypes are particularly relevant to Type 1 Diabetes, as exhaustion-like signatures have been associated with clinical response to T cell targeted immunotherapeutics teplizumab (α-CD3), alefacept (LFA3-Ig), and Anti-thymocyte Globulin (ATG). However, there is currently a lack of data regarding the impact of this locus on peripheral T cell phenotype and function in humans with and at risk for T1D. I hypothesize that BACH2 and candidate T1D risk polymorphisms modulate peripheral tolerance mechanisms and autoreactive T cell phenotype, function, and repertoire clonality in T1D. Indeed, my preliminary data indicate that both rare familial and T1D-associated BACH2 variants drive enhanced effector CD8+ T cell phenotypes in peripheral blood and the pancreas draining lymph nodes (pLN), which is corroborated by CRISPR/Cas9 mediated BACH2 knockout in primary human T cells. The objective of the proposed studies is to uncover the molecular mechanisms driving enhanced effector function and to better understand the role of BACH2 in regulating autoreactive function across tissues. In Aim 1, we will perform BACH2 KO and base editing of rs72928038G>A in polyclonal and engineered autoreactive T cells to investigate the impact on effector function, T cell polarization, and exhaustion and their molecular drivers using in vitro functional assays and multimodal genomics. In Aim 2, we will utilize bulk T cell receptor (TCR) sequencing data from pLN and spleen to understand the impact of rs72928038G>A on TCR clonality, autoreactive clone frequency and TCR features such as amino acid usage and charge and CDR3 length. We will investigate the impact of BACH2 on receptor avidity and antigen responsiveness with in vitro functional assays using gene and TCR engineered cells. Aim 3 focuses on establishing live human lymph node slice and organoid microphysiological systems to understand the role of BACH2 in regulating immune phenotypes and autoreactive function in situ. I expect my findings to expand our knowledge of mechanisms of genetic risk, inform on novel targetable pathways to enhance immune tolerance and support precision medicine selection strategies for immunotherapies in T1D.


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 = $89,999 )
2026	2026	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	1	8/18/2026	NEW	$89,999
														Subtotal = $89,999

Grand Total All Awards = $89,999

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Investigating the role of T1D candidate locus BACH2 in the regulation of peripheral tolerance mechanisms in T1D

Award Number: K99AI202086

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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