# Manipulating & imaging nutrient micro-milieux as B cells effect humoral immunity

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $525,381

## Abstract

Project Summary
Generating antibodies, refining their qualities, and creating durable humoral memory are crucial parts of adaptive
immunity. The capacity of vaccines to protect against microbes draws on each facet of these processes, but even
for some approved and useful vaccines the efficacy is needs to be better. Accordingly, it is vital to decipher key
cellular and molecular processes that affect antibody (Ab) qualities. Major efforts are directed toward the
identification of ways in which intracellular sensors, mediators of intermediary metabolism, and metabolites proper
alter immune cell differentiation or function. It has long been known that malnutrition undermines immune
defenses against infection, and a body of work has suggested that protein deficiency may decrease effective Ab
responses. Nutrient supply is intrinsically linked to intracellular sensors such as mTORC1 and programming of
cellular metabolism in immune cells. For instance, experimental models of isolated protein deficiency have
documented decreases in venous concentrations of amino acids (a.a.) and lower mTORC1 activity in freshly
isolated organs from the malnourished rodents. Our work on mTORC1 in B cells found antibody responses to be
altered by B cell-restricted haplo-insufficiency of Raptor, with partially reduced activity similar in magnitude to that
reported in the setting of protein deprivation. Moreover, we – and others in parallel – uncovered evidence of
variegated hypoxia in the white pulp and lymphoid follicles after immunization and formation of germinal centers.
Preliminary in vitro and in vivo experiments provide evidence that (a) glutamine, at the physiological concentration
of non-inflamed interstitia, is limiting for fully efficient switching to IgG1 and for plasma cell differentiation, and (b)
glutaminolysis (the conversion of glutamine to glutamate, and then α-ketoglutarate) can be limiting for these
processes. These findings are the premise for the overarching model of this application: that nutrients may be
present in follicles at concentrations where either increases or further decreases alter the nature of the antibody
response as it draws on lymphocyte proliferation and function. Accordingly, in Aim 1 we will test the impact on Ab
responses of reducing a.a. supply to or utilization by mature B cells. Aim 2 will identify consequences for
metabolic and epigenetic programming of the B cells in which glutamine supply or glutaminolysis are restricted,
alone or with reduced glucose oxidation capacity. An implication of the model is that increased circulating a.a. – or
even just glutamine – could enhance outcomes of immunization. In Aim 3, we will use a newly identified endocrine
approach to test if hyperaminoacidemia increases interstitial glutamine and yields greater Ab responses or
humoral memory. As a novel facet of the experiments, we will leverage a state-of the-art development in imaging
mass spectrometry (IMS) to assess glutamine and selected metabo...

## Key facts

- **NIH application ID:** 10306395
- **Project number:** 5R01AI149722-03
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Mark R Boothby
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $525,381
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10306395

## Citation

> US National Institutes of Health, RePORTER application 10306395, Manipulating & imaging nutrient micro-milieux as B cells effect humoral immunity (5R01AI149722-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10306395. Licensed CC0.

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