HLA risk alleles cause type 1 diabetes by modifying the selection of t cell receptors that recognize pancreatic beta cell antigens
Active Project Grant Awarded Last action
- Award ID
- F30AI176724
- Recipient
-
President And Fellows Of Harvard College UEI JDLVAVGYJQ21 Part of Harvard College President & Fellows Of
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $436,990
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 93% complete
- Place of performance
- Boston, MA 02115, USA
Award details come from USAspending.gov.
Description
- Abstract
- Type 1 diabetes (T1D) is a debilitating, lifelong disease which currently affects 20 million people worldwide. Multiple lines of evidence have shown that t cells target and destroy pancreatic SS-cells in individuals with T1D. Though several key autoantigens have been identified, t cell antigen receptors (tcrs) that recognize these antigens circulate in most individuals, including those who never get T1D. Genetic studies have shown that T1D is highly heritable, with HLA genes accounting for more risk than any other locus. We and others have shown that HLA variation influences which TCR sequences survive thymic selection. TCR sequence has a documented effect on t cell state: select v and j genes give rise to mucosal-associated invariant t (mait) cells and hydrophobic CDR3SS residues promote regulatory t cell (treg) fate (lagattuta ET AL., NAT. Immunol., 2022). Because each t cell's TCR sequence is randomly acquired through v(d)j recombination prior to t cell differentiation, these relationships are likely causal. We propose that any given TCR has a functional potential: a distinct likelihood of differentiation over all t cell states. The proposed research will test the hypothesis that HLA risk alleles cause T1D by selecting SS-cell- specific tcrs with inflammatory functional potential. Such tcrs would promote the differentiation of SS- cell-specific t cells toward pathogenic, effector memory cell states, analogous to the way mucosal-associated invariant t cell (mait) tcrs drive acquisition of the mait transcriptional phenotype. Through rigorous statistical modeling, i will trace the impact of T1D HLA risk on SS-cell-specific t cells: from HLA selection of TCR patterns to the influence of TCR patterns on t cell state. Specifically, the study aims to (1) define which TCR sequence features influence t cell state, and (2) assess the impact of HLA risk alleles on the pancreatic SS-cell specific TCR repertoire. The translational impact of robustly identifying SS-cell-specific tcrs is clear: this could help therapeutically target autoreactive t cells, could inform engineering of SS-cell-specific tregs, and would enable clinical monitoring of the SS-cell-specific immune response longitudinally. More broadly, this work will provide a much-needed bioinformatic tool to cluster tcrs by antigen specificity, and will produce novel insights into how TCR sequence features instruct t cell fate. The proposed training plan will enable me to: (a) develop skills in computational methods development, (b) cultivate statistical expertise for functional genomics and human genetics, (c) gain familiarity with the generation of high-throughput genomic data, (d) learn the immunological foundations and clinical manifestations of autoimmune disease, and (e) sharpen professional scientific skills such as oral presentation and manuscript writing. A resource-rich training environment with close mentorship from experts in bioinformatic methods development, HLA genetics, TCR sequences, and t cell states in the context of autoimmunity will prepare me to become a successful physician-scientist leader in computational immunology.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $576 | |
| Amendment | $54,538 | |
| Amendment | $54,538 | |
| Amendment | $564 | |
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| Amendment | $564 | |
| Amendment | $53,974 | |
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| Amendment | $1,280 | |
| Amendment | $1,280 | |
| Amendment | $40,291 | |
| Amendment | $0 | |
| Amendment | $40,291 | |
| Amendment | $0 | |
| Amendment | $40,291 | |
| Amendment | $0 | |
| Original award | $40,291 |
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Quick answers
Who received award F30AI176724?
F30AI176724 was awarded to President And Fellows Of Harvard College by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on June 5, 2024.
How much is award F30AI176724 worth?
$436,990 has been obligated on F30AI176724.
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