l-Citrulline Metabolism in Mice Augments CD4+ T Cell Proliferation and Cytokine Production In Vitro, and Accumulation in the Mycobacteria-Infected Lung

Abstract

Activation, recruitment, and effector function of T lymphocytes are essential for control of mycobacterial infection. These processes are tightly regulated in T cells by the availability of l-arginine within the microenvironment. In turn, mycobacterial infection dampens T cell responsiveness through arginase induction in myeloid cells, promoting sequestration of l-arginine within the local milieu. Here, we show T cells can replenish intracellular l-arginine through metabolism of l-citrulline to mediate inflammatory function, allowing anti-mycobacterial T cells to overcome arginase-mediated suppression. Furthermore, T cell l-citrulline metabolism is necessary for accumulation of CD4+ T cells at the site of infection, suggesting this metabolic pathway is involved during anti-mycobacterial T cell immunity in vivo. Together, these findings establish a contribution for l-arginine synthesis by T cells during mycobacterial infection, and implicate l-citrulline as a potential immuno-nutrient to modulate host immunity.

l-Arginine Synthesis from l-Citrulline in Myeloid Cells Drives Host Defense against Mycobacteria In Vivo

“…Hematopoieticderived adaptive immune cells may also require L-ARG synthesis during infection. Yet, eliminating L-ARG synthesis solely in CD4 + and CD8 + T cells (using CD4-cre conditional knockouts) does not alter mycobacterial burden (18). Collectively, these data show that L-CIT metabolism is necessary within myeloid cells to drive host defense against mycobacterial infection.…”

“…Yet if L-ARG synthesis is necessary in other cells, its loss in nonmyeloid populations does not alter mycobacterial burden in the lung (i.e., comparing deletion by Lyz2 cre/cre to Tie2cre) at the 8-wk end point of these studies. Regardless, with the known importance of L-ARG synthesis in endothelial cells (21,22,34,35) and T cells (17,18,(36)(37)(38), further investigation into how L-CIT metabolism affects these and other cell populations during infection warrants investigation. Considering the fluctuation of L-CIT in the lung (Fig.…”

“…Antimycobacterial NO production and T cell activity can be fueled by a related amino acid, L-citrulline (L-CIT) (17)(18)(19)(20). L-CIT can be acquired from the diet or during metabolic processing of L-ARG (via NO synthases) or L-ORN (via ornithine carbamoyl transferase) (21).…”

l-Citrulline Supplementation: Impact on Cardiometabolic Health

“…In addition to its impact on innate immunity, l -citrulline supplementation appears to regulate adaptive immunity and further reduce cytokine-induced low-grade inflammation. Emerging research on immune energetics has highlighted the importance of metabolic regulation on adaptive immune function [ 74 ], and recent studies have placed l -citrulline at the center of CD4+ T-cell metabolism, function, and survival [ 75 ]. Considering the equal importance of l -arginine in CD8+ T-cell metabolic profile in vivo [ 76 ], it can be hypothesized that l -citrulline supplementation will directly and indirectly modulate the metabolism of innate and adaptive immune cells, improve the efficiency of immune responses to pathogen and reduce both the magnitude and duration of inflammatory responses in response to antigenic challenges.…”

Tuberculosis causes highly conserved metabolic changes in human patients, mycobacteria-infected mice and zebrafish larvae

“…The only consistently decreased metabolite of these urea cycle intermediates in all three species is citrulline. Interestingly, previous studies have shown that arginine depletion as a result of arginase activity can be replenished from citrulline in macrophages and T-cells and thereby plays a role in immune defense 37,38 . Although in zebrafish larvae, the T-cells are not yet developed 39 , functional macrophages that can express arginase are present 40 .…”