Synthetic auxotrophy reveals metabolic regulation of plasma cell generation, affinity maturation, and cytokine receptor signaling
7 affiliations
- 1Department of Pathology, Microbiology and Immunology, Molecular Pathogenesis Division, Vanderbilt University Medical Center, Nashville, United States
- 2Cancer Biology Program, Vanderbilt University, Nashville, United States
- 3Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott and White Research Institute, Dallas, United States
- 4Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, United States
- 5Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, United States
- 6Vanderbilt Center for Infection, Inflammation, Immunology (VI4), Vanderbilt University Medical Center, Nashville, United States
- 7Department of Medicine, Rheumatology and Immunology Division, Vanderbilt University Medical Center, Nashville, United States
Abstract
The proliferation and development of activated B lymphocytes into antibody (Ab)-secreting plasma cells are critical determinants of humoral immunity and sustain certain autoimmune diseases. Specific pathways and substrate supplies in intermediary metabolism influence lymphocyte differentiation and function. We now show that although stringent restriction of glutamine supply decreases B cell proliferation and differentiation into plasma cells, glutaminolysis – a major metabolic use of this amino acid – was only conditionally crucial in B cells and the Ab responses derived from them. Gls, the gene encoding the main glutaminase of lymphocytes, promoted anti-NP Ab responses at the primary and recall phases if either glucose uptake into mouse B cells or pyruvate into their mitochondria was also impaired. Otherwise, it was dispensable. This synthetic auxotrophy, that is, the conditional requirement of glutaminase for processes in addition to survival, involved supporting progressive expansion of mitochondrial respiration followed by plasma cell differentiation. Surprisingly, impairment of glutaminase and the mitochondrial pyruvate channel decreased IL-21 stimulation of STAT3 phosphorylation as well as interferon stimulation of STAT1 activation. Together, our findings establish a powerful collaboration of metabolic pathways in programming increased respiration and the development of Ab-secreting cells, but also reveal modulation of cytokine receptor signaling by metabolism.
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BibTeX
@article{cho2026synthetic,
title = {{Synthetic auxotrophy reveals metabolic regulation of plasma cell generation, affinity maturation, and cytokine receptor signaling}},
author = {Sung Hoon Cho and Shawna K Brookens and Ariel L Raybuck and Kaylor Meyer and Yeeun Paik and Jennie Hamilton and Jingxin Li and Karel Kalecky and Chloe Park and Juyeon Lim and Sakeenah L Hicks and John Karijolich and Teodoro H Bottiglieri and Jeffrey C Rathmell and Denis Mogilenko and Christopher D Scharer and Mark R Boothby},
journal = {eLife},
year = {2026},
month = oct,
doi = {10.7554/elife.107627},
url = {https://elifesciences.org/articles/107627},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Synthetic auxotrophy reveals metabolic regulation of plasma cell generation, affinity maturation, and cytokine receptor signaling
AU - Sung Hoon Cho
AU - Shawna K Brookens
AU - Ariel L Raybuck
AU - Kaylor Meyer
AU - Yeeun Paik
AU - Jennie Hamilton
AU - Jingxin Li
AU - Karel Kalecky
AU - Chloe Park
AU - Juyeon Lim
AU - Sakeenah L Hicks
AU - John Karijolich
AU - Teodoro H Bottiglieri
AU - Jeffrey C Rathmell
AU - Denis Mogilenko
AU - Christopher D Scharer
AU - Mark R Boothby
PY - 2026
DA - 2026/10/29
JO - eLife
DO - 10.7554/elife.107627
UR - https://elifesciences.org/articles/107627
AB - The proliferation and development of activated B lymphocytes into antibody (Ab)-secreting plasma cells are critical determinants of humoral immunity and sustain certain autoimmune diseases. Specific pathways and substrate supplies in intermediary metabolism influence lymphocyte differentiation and function. We now show that although stringent restriction of glutamine supply decreases B cell proliferation and differentiation into plasma cells, glutaminolysis – a major metabolic use of this amino acid – was only conditionally crucial in B cells and the Ab responses derived from them. Gls, the gene encoding the main glutaminase of lymphocytes, promoted anti-NP Ab responses at the primary and recall phases if either glucose uptake into mouse B cells or pyruvate into their mitochondria was also impaired. Otherwise, it was dispensable. This synthetic auxotrophy, that is, the conditional requirement of glutaminase for processes in addition to survival, involved supporting progressive expansion of mitochondrial respiration followed by plasma cell differentiation. Surprisingly, impairment of glutaminase and the mitochondrial pyruvate channel decreased IL-21 stimulation of STAT3 phosphorylation as well as interferon stimulation of STAT1 activation. Together, our findings establish a powerful collaboration of metabolic pathways in programming increased respiration and the development of Ab-secreting cells, but also reveal modulation of cytokine receptor signaling by metabolism.
SN - 2050-084X
ER -