Functional overlap of inborn errors of immunity and metabolism genes defines T cell metabolic vulnerabilities
Inborn errors of metabolism (IEMs) and immunity (IEIs) are Mendelian diseases in which complex phenotypes and patient rarity have limited clinical understanding. Whereas few genes have been annotated as contributing to both IEMs and IEIs, immunometabolic demands suggested greater functional overlap. Here, CRISPR screens tested IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable previously unappreciated crossover. Analysis of IEMs showed that N-linked glycosylation and the hexosamine pathway enzyme <i>Gfpt1</i> are critical for T cell expansion and function. Further, T helper (T<sub>H</sub>1) cells synthesized uridine diphosphate <i>N</i>-acetylglucosamine more rapidly and were more impaired by <i>Gfpt1</i> deficiency than T<sub>H</sub>17 cells. Screening IEI genes found that <i>Bcl11b</i> promotes the CD4 T cell mitochondrial activity and <i>Mcl1</i> expression necessary to prevent metabolic stress. Thus, a high degree of functional overlap exists between IEM and IEI genes, and immunometabolic mechanisms may underlie a previously underappreciated intersection of these disorders.
Authors
- Emilie L. Fisher (ORCID: https://orcid.org/0000-0001-9186-7512)
- Gabriella L. Robertson (ORCID: https://orcid.org/0000-0002-8729-8334)
- Caroline Bodnya (ORCID: https://orcid.org/0000-0002-3682-3469)
- Ryan D. Sheldon (ORCID: https://orcid.org/0000-0002-1573-9719)
- Russell G. Jones (ORCID: https://orcid.org/0000-0003-2250-4675)
- Ayaka Sugiura (ORCID: https://orcid.org/0000-0001-5326-5019)
- Channing Chi (ORCID: https://orcid.org/0000-0003-4987-4764)
- Jeffrey C. Rathmell (ORCID: https://orcid.org/0000-0002-4106-3396)
- KayLee K. Steiner (ORCID: https://orcid.org/0000-0003-2188-6376)
- Erin Q. Jennings (ORCID: https://orcid.org/0000-0002-6991-6098)
- Vivian Gama (ORCID: https://orcid.org/0000-0002-1201-1394)
- Gabriel A. Needle (ORCID: https://orcid.org/0000-0002-8092-1074)
- Janet Markle (ORCID: https://orcid.org/0000-0003-2189-4368)
- Andrew R. Patterson (ORCID: https://orcid.org/0000-0002-5177-5055)
Institutions
- Van Andel Institute (US)
- Vanderbilt University (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Science Immunology
- Published
- 2024-08-16
- DOI
- https://doi.org/10.1126/sciimmunol.adh0368
- Citations
- 7
- Primary Topic
- Immunodeficiency and Autoimmune Disorders
- Type
- article
- Field-Weighted Citation Impact
- 1.68
Funders
- Pfizer
- Vanderbilt University
- Lupus Research Alliance
- Vanderbilt University Medical Center
- Incyte
- Calithera Biosciences
- National Institutes of Health
- Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center
- National Cancer Institute