Selective requirement of glycosphingolipid synthesis for natural killer and cytotoxic T cells

Tasha A Morrison; Jaelyn Vigee; Kevin A Tovar; Taylor A Talley; Adriana M Mujal; Mari Kono; Rachael Philips; Hiroyuki Nagashima; Stephen R Brooks; Hannah Dada; Isaiah Rozich; Kelly Hudspeth; Colleen M Lau; Chen Yao; Giuseppe Sciumè; Hong-Wei Sun; Juan S Bonifacino; Yuka Kanno; Michael L Dustin; Davide Randazzo; Richard L Proia; Joseph C Sun; Han-Yu Shih; John J O'Shea

doi:10.1016/j.cell.2025.04.007

Selective requirement of glycosphingolipid synthesis for natural killer and cytotoxic T cells

Cell. 2025 Jun 26;188(13):3497-3512.e16. doi: 10.1016/j.cell.2025.04.007. Epub 2025 Apr 29.

Authors

Tasha A Morrison¹, Jaelyn Vigee², Kevin A Tovar², Taylor A Talley², Adriana M Mujal³, Mari Kono⁴, Rachael Philips⁵, Hiroyuki Nagashima⁵, Stephen R Brooks⁶, Hannah Dada⁵, Isaiah Rozich⁵, Kelly Hudspeth⁵, Colleen M Lau⁷, Chen Yao⁸, Giuseppe Sciumè⁹, Hong-Wei Sun⁶, Juan S Bonifacino¹⁰, Yuka Kanno⁵, Michael L Dustin¹¹, Davide Randazzo¹², Richard L Proia⁴, Joseph C Sun³, Han-Yu Shih¹³, John J O'Shea¹⁴

Affiliations

¹ Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA; Lymphocyte Signaling Unit, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD, USA. Electronic address: tasha.morrison@nih.gov.
² Lymphocyte Signaling Unit, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD, USA.
³ Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁴ Genetics of Development and Disease Section, Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA.
⁵ Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
⁶ Biodata Mining and Discovery Section, NIAMS, NIH, Bethesda, MD, USA.
⁷ Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, USA.
⁸ Department of Immunology, University of Texas Southwestern Medical School, Dallas, TX, USA.
⁹ Department of Molecular Medicine, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, "Sapienza" University of Rome, Rome, Italy.
¹⁰ Division of Neurosciences and Cellular Structure, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
¹¹ Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
¹² Light Imaging Section, NIAMS, NIH, Bethesda, MD, USA.
¹³ Neuro-immune Regulome Unit, National Eye Institute, NIH, Bethesda, MD, USA.
¹⁴ Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA. Electronic address: john.oshea@nih.gov.

PMID: 40306279
PMCID: PMC12204804 (available on 2026-06-26)
DOI: 10.1016/j.cell.2025.04.007

Abstract

Cell identity genes that exhibit complex regulation are marked by super-enhancer (SE) architecture. Assessment of SEs in natural killer (NK) cells identified Ugcg, encoding the enzyme responsible for glycosphingolipid (GSL) synthesis. Conditional deletion of Ugcg in early hematopoiesis abrogated NK cell generation while sparing other lineages. Pharmacological inhibition of UGCG disrupted cytotoxic granules and cytotoxicity, reduced expansion after viral infection, and promoted apoptosis. B4galt5 transcribes an enzyme downstream of UGCG and possesses SE structure. Addition of its product, lactosylceramide (LacCer), reversed apoptosis due to UGCG inhibition. By contrast, complex GSLs, such as asialo-GM1, were not required for NK cell viability and granule integrity. Ugcg and B4galt5 were upregulated in CD8⁺ T cells during viral infection, correlating with the acquisition of cytotoxic machinery. Antigen-specific CD8⁺ T cells lacking Ugcg failed to expand during infection. Our study reveals a selective and essential role of GSL metabolism in NK and CD8⁺ T cell biology.

Keywords: B4galt5; CD8(+) T cells; Ugcg; cytotoxic granules; glycosphingolipids; immunometabolism; lactosylceramide; lymphocytes; natural killer cells; super-enhancers.

Published by Elsevier Inc.

MeSH terms

Animals
Apoptosis
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
Galactosyltransferases / genetics
Galactosyltransferases / metabolism
Glycosphingolipids* / biosynthesis
Killer Cells, Natural* / cytology
Killer Cells, Natural* / immunology
Killer Cells, Natural* / metabolism
Mice
Mice, Inbred C57BL
T-Lymphocytes, Cytotoxic* / cytology
T-Lymphocytes, Cytotoxic* / immunology
T-Lymphocytes, Cytotoxic* / metabolism

Substances

Glycosphingolipids
Galactosyltransferases
UDP-galactose-lactosylceramide alpha 1-4-galactosyltransferase

Abstract

MeSH terms

Substances

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