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Review
. 2012 Sep;249(1):135-57.
doi: 10.1111/j.1600-065X.2012.01149.x.

Amino acid catabolism: a pivotal regulator of innate and adaptive immunity

Tracy L McGaha  1 , Lei Huang, Henrique Lemos, Richard Metz, Mario Mautino, George C Prendergast, Andrew L Mellor
Affiliations
Review

Amino acid catabolism: a pivotal regulator of innate and adaptive immunity

Tracy L McGaha et al. Immunol Rev. 2012 Sep.

Abstract

Enhanced amino acid catabolism is a common response to inflammation, but the immunologic significance of altered amino acid consumption remains unclear. The finding that tryptophan catabolism helped maintain fetal tolerance during pregnancy provided novel insights into the significance of amino acid metabolism in controlling immunity. Recent advances in identifying molecular pathways that enhance amino acid catabolism and downstream mechanisms that affect immune cells in response to inflammatory cues support the notion that amino acid catabolism regulates innate and adaptive immune cells in pathologic settings. Cells expressing enzymes that degrade amino acids modulate antigen-presenting cell and lymphocyte functions and reveal critical roles for amino acid- and catabolite-sensing pathways in controlling gene expression, functions, and survival of immune cells. Basal amino acid catabolism may contribute to immune homeostasis that prevents autoimmunity, whereas elevated amino acid catalytic activity may reinforce immune suppression to promote tumorigenesis and persistence of some pathogens that cause chronic infections. For these reasons, there is considerable interest in generating novel drugs that inhibit or induce amino acid consumption and target downstream molecular pathways that control immunity. In this review, we summarize recent developments and highlight novel concepts and key outstanding questions in this active research field.

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Conflict of interest statement

T.L.M., L.H., and H.L. have no conflicts to declare.

Figures

Fig. 1
Fig. 1. Amino acid catabolism and altered immune cell functions
Cells expressing enzymes that catablize amino acids (top) create local conditions where immune cells (bottom) experience reduced access to amino acids triggering effects on mTOR and GCB2 pathways that sense levels of amino acids inside cells. Trp depletion and Kyn production trigger cellular responses via GCN2- and AhR-signaling pathways, respectively, to promote regulatory responses by immune cells as indicated.
Fig. 2
Fig. 2. GCN2 and AhR signaling
Trp depletion and Kyn production trigger cellular responses via GCN2- and AhR-signaling pathways, respectively, to promote regulatory responses by immune cells. See text for details.
Fig. 3
Fig. 3. Potential physiologic effects of IDO-expressing DCs on Trp levels in lymphoid follicles
The model posits how small cohorts of splenic MZ DCs expressing IDO may create regions of low Trp reserves in lymphoid follicles effecting T cells, B cells, and macrophages and DCs inside the follicle to generate immune suppression and tolerance.
See this image and copyright information in PMC

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