Glutamine requirement of proliferating T lymphocytes

doi:10.1016/S0899-9007(97)83008-0

Nutrition

Volume 13, Issues 7–8, July–August 1997, Pages 646-651

https://doi.org/10.1016/S0899-9007(97)83008-0 Get rights and content

Abstract

Glutamine is required for lymphocyte proliferation but the site of glutamine action is not yet known. In this study, the effect of glutamine on key events that occur during lymphocyte activation [interleukin-2 (IL-2) production, IL-2 use, IL-2 receptor expression, transferrin receptor expression] was investigated. Rat or mouse spleen lymphocytes were cultured in the presence of the T-cell mitogen concanavalin A (Con A) and various concentrations of glutamine. There was a trend (not significant) for the ratio of CD4⁺:CD8⁺ spleen lymphocytes to increase (from 1.9 to 2.6) as the concentration of glutamine in culture medium increased from 0 to 2 mmol/L. As the concentration of glutamine increased, there was an increase in the proportion of cells expressing the IL-2 receptor (from 30 to 45%) and the transferrin receptor (from 34% to 55%). As the concentration of glutamine increased there was a 2.7-fold increase in the concentration of IL-2 in the culture medium. The IL-2 concentration was decreased when an IL-2 receptor-blocking antibody was included in the culture medium; the IL-2 concentrations measured were taken to indicate the initial Con A-stimulated production of IL-2. In these conditions, the IL-2 concentration in the medium increased 39-fold as the glutamine concentration increased. The use of IL-2 by an IL-2-dependent cell line was dependent on the glutamine concentration in the culture medium. Thus, all four components of lymphocyte activation investigated (IL-2 production, IL-2 use, IL-2 receptor expression, transferrin receptor expression) were dependent on the concentration of glutamine present in the culture medium. Thus, glutamine might provide an early signal in the lymphocyte activation process.

References (46)

E Robey et al.
T-cell activation: integration of signals from the antigen receptor and costimulatory molecules
Immunol Today
(1995)
AM O'Rourke et al.
Glucose, glutamine and ketone body utilization by resting and concanavalin A activated rat splenic lymphocytes
Biochim Biophys Acta
(1989)
MSM Ardawi
Glutamine and glucose metabolism in human peripheral lymphocytes
Metabolism
(1988)
K Brand et al.
Metabolism of glutamine in lymphocytes
Metabolism
(1989)
M Parry-Billings et al.
Does glutamine contribute to immunosuppression after major burns?
Lancet
(1990)
PC Calder
Glutamine and the immune system
Clin Nutr
(1994)
E Roth et al.
Metabolic disorders in severe abdominal sepsis: glutamine deficiency in skeletal muscle
Clin Nutr
(1982)
P Stehle et al.
Effect of parenteral glutamine peptide supplements on muscle glutamine loss and nitrogen balance after surgery
Lancet
(1989)
WW Souba et al.
Oral glutamine reduces bacterial translocation following abdominal radiation
J Surg Res
(1990)
RRW van der Hulst et al.
Glutamine and the preservation of gut integrity
Lancet
(1993)

JE Weiel et al.

Quiescent lymphocytes express intracellular transferrin receptors

Biochem Biophys Res Commun

(1984)

S Maeda et al.

Cloning of interleukin 2 mRNAs from human tonsils

Biochem Biophys Res Commun

(1983)

A Weiss

T lymphocyte activation

GR Crabtree et al.

Signal transmission between plasma membrane and nucleus of T lymphocytes

Annu Rev Biochem

(1994)

KA Smith

Interleukin-2: inception, impact and implications

Science

(1988)

D Cantrell et al.

The interleukin-2 T-cell system: a new cell growth model

Science

(1984)

TA Hamilton

Regulation of transferrin receptor expression in concanavalin A stimulated and gross virus transformed rat lymphoblasts

J Cell Physiol

(1982)

K Brand

Glutamine and glucose metabolism during thymocyte proliferation

Biochem J

(1985)

MSM Ardawi et al.

Glutamine metabolism in lymphocytes of the rat

Biochem J

(1983)

G Wu et al.

Elevated glutamine metabolism in splenocytes from spontaneously diabetic BB rats

Biochem J

(1991)

PC Calder

Fuel utilisation by cells of the immune system

Proc Nutr Soc

(1995)

Z Szondy et al.

The effect of glutamine concentration on the activity of carbamoyl-phosphate synthase II and on the incorporation of [³H]thymidine into DNA in rat mesenteric lymphocytes stimulated by phytohaemagglutinin

Biochem J

(1989)

M Griffiths et al.

The effect of glutamine on murine splenic leukocyte responses to T and B cell mitogens

Immunol Cell Biol

(1990)

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Amino acids are known to contribute to T cell differentiation and cytokine production [32–46]. Moreover, CD4+ T cells, unlike common somatic cells, depend on the extracellular pool for amino acids, including nonessential amino acids, such as glutamine [44–46], arginine [47–49], leucine [50,51], serine [52,53], alanine [54], cysteine [55,56], and tryptophan [57,58]. These amino acids are important substrates for energy and protein synthesis in activated T cells that undergo rapid proliferation and produce high levels of cytokines.
Excessive activation of CD4⁺ T cells increases cytokine production substantially and induces immune-mediated diseases. Procyanidins are polyphenols with anti-inflammatory properties. Procyanidin B2 (PCB2) gallate [specifically, PCB2 3,3′′-di-O-gallate (PCB2DG)] inhibits cytokine production through the suppression of glycolysis via mammalian target of rapamycin (mTOR) in T cells. Several amino acids play critical roles in T cell activation, especially glutamine, which is important in mTOR signaling and interferon-γ (IFN-γ) production in CD4⁺ T cells. However, the mechanisms underlying the effects of PCB2DG, including its interaction partners, have yet to be clarified. In the present study, the mechanisms underlying the inhibitory effect of PCB2DG on IFN-γ through glutamine metabolism regulation were investigated. We found that PCB2DG treatment reduced intracellular glutamine levels in CD4⁺ T cells, whereas the addition of glutamine abrogated the inhibitory effects of PCB2DG on IFN-γ production. The PCB2DG-induced reduction in intracellular glutamine accumulation led to the upregulated expression of activating transcription factor 4, which was induced by the cytoprotective signaling pathway in the amino acid response. In addition, the mRNA and protein expression levels of alanine serine cysteine transporter 2 (ASCT2), a major glutamine transporter in CD4⁺ T cells, were not altered by PCB2DG treatment. Further analysis using a target identification strategy revealed that PCB2DG binds to ASCT2, suggesting that PCB2DG interacts directly with this major glutamine transporter to inhibit glutamine influx. Overall, this study indicates that ASCT2 is a novel target protein of a dietary polyphenol and provides new insights into the mechanism underlying the immunomodulatory effects of polyphenols.
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IL-2, IL-4, and IL-6 are powerful immune mediators that promote the proliferation of immune cells (Zhu et al., 2010; Suna et al., 2014; Alexander et al., 2021). Parveen and Philip (1997) showed that Gln helps to maintain body immune function by enhancing lymphocyte proliferation and activation, the ratio of CD4+ and CD8+ lymphocytes, and the release of proinflammatory cytokines. In this study, after treatment with Gln, the content of plasma IL-2 in the high-concentrate fattening lambs significantly increased on days 15, 30, and 45 (P < 0.05).
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Glutaminolysis is a major energy-producing process for proliferating cells, including activated T cells (Newsholme et al., 1999), by supplying α-ketoglutarate (αKG) to the TCA cycle, via glutamate. Glutamine is required for T cell activation (Yaqoob and Calder, 1997), as T cells cultured without glutamine cannot proliferate or produce IL-2 or IFN-γ (Carr et al., 2010). Supplementation with asparagine, proline, or glutamate, which can be metabolized to glutamine, does not recue proliferation or cytokine defects due to glutamine withdrawal, indicating that acquisition of extracellular glutamine, and not its intracellular generation, is the key regulatory event.
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Basic nutritional investigationsGlutamine requirement of proliferating T lymphocytes

Abstract

Immunol Today

Biochim Biophys Acta

Metabolism

Metabolism

Lancet

Clin Nutr

Clin Nutr

Lancet

J Surg Res

Lancet

Biochem Biophys Res Commun

Biochem Biophys Res Commun

T lymphocyte activation

Signal transmission between plasma membrane and nucleus of T lymphocytes

Annu Rev Biochem

Interleukin-2: inception, impact and implications

Science

The interleukin-2 T-cell system: a new cell growth model

Science

Regulation of transferrin receptor expression in concanavalin A stimulated and gross virus transformed rat lymphoblasts

J Cell Physiol

Glutamine and glucose metabolism during thymocyte proliferation

Biochem J

Glutamine metabolism in lymphocytes of the rat

Biochem J

Elevated glutamine metabolism in splenocytes from spontaneously diabetic BB rats

Biochem J

Fuel utilisation by cells of the immune system

Proc Nutr Soc

The effect of glutamine concentration on the activity of carbamoyl-phosphate synthase II and on the incorporation of [3H]thymidine into DNA in rat mesenteric lymphocytes stimulated by phytohaemagglutinin

Biochem J

The effect of glutamine on murine splenic leukocyte responses to T and B cell mitogens

Immunol Cell Biol

Basic nutritional investigations
Glutamine requirement of proliferating T lymphocytes

The effect of glutamine concentration on the activity of carbamoyl-phosphate synthase II and on the incorporation of [³H]thymidine into DNA in rat mesenteric lymphocytes stimulated by phytohaemagglutinin