The mediation of transplant rejection by allogeneic immune responses remains the main impediment to prolonged graft survival and to the achievement of tolerance. Adequate cell activation and differentiation is required for efficient immune responses to develop, and the balance between regulatory and effector cells serves as a key determinant of transplantation outcome. Understanding of the different signalling pathways and transcriptional patterns which characterize particular immune cell subsets led to the identification of novel targets for the improved monitoring and treatment of transplanted patients. More recently, it has emerged that the reprogramming of complex intracellular metabolic pathways also plays a crucial part in shaping immune cell function.1 As a consequence, attention has turned toward the interrogation and manipulation of the metabolic status of immune cells with a view to developing novel monitoring tools and therapeutic approaches.
Because of their lower metabolic requirements, naive T cells preferentially rely on glycolysis and the tricarboxylic acid cycle for survival. Upon activation, metabolic reprogramming and alterations in nutrient uptake are necessary to meet the biosynthetic needs associated with cell division and acquisition of effector functions. This early activation is characterized by an increased glycolytic rate, glutamine metabolism, and the pentose phosphate pathway, combined with the synthesis of proteins, lipids, and nucleic acids. Interestingly, the metabolic programs used by the different T-cell subpopulations appear to have distinct features that are essential to support their lineage reinforcement and function.2 In broad terms, although effector T cells with enhanced proliferation, including type 1 and type 17 T helper cells, and cytotoxic cluster of differentiation (CD)8+ T cells, use glycolysis and glutaminolysis to promote proliferation and cytokine production, differentiated regulatory T (Treg) cells and memory CD8+ T cells use the tricarboxylic acid cycle and fatty acid oxidation to enhance their function and survival. The metabolic reprogramming undertaken is determined to an extent by the nutrients available and by the regulation of enzyme networks. The functional fate of T cells after antigen recognition is highly dependent on the asymmetric distribution of the mechanistic target of rapamycin (mTOR), for instance, the activation of which promotes glycolysis and facilitates effector T-cell differentiation.3
The distinct metabolic features and requirements observed in effector and suppressive cell subsets offer promising opportunities for selective regulation of the immune responses in transplantation. It has been reported that simultaneously blocking glycolysis and glutamine metabolism can prevent allograft rejection in models of skin and heart transplantation.4 Interestingly, this approach was noted to suppress CD4+ and CD8+ effector T cells while promoting the generation of allospecific Treg cells. These data suggest that the inhibition of metabolic pathways can exert cellular selectivity by preferentially affecting those cells with the greatest demand for that particular metabolic process.
In this issue of Transplantation, Tanimine and colleagues5 provide a comprehensive overview of the emerging field of immunometabolism in transplantation. The report provides a detailed description of the particular metabolic programs associated with the different T-cell subsets and highlights several approaches towards targeting their function. In light of their salience in immunoregulation, particular attention is paid to the metabolic control of Treg cells and their subsets. Their work clearly outlines the ways in which these pathways can be targeted using different approaches including the modulation of signalling, the inhibition of enzymes and mitochondrial reactions, and the alteration of epigenetic traits. Importantly, choosing the optimal metabolic target will determine the cellular selectivity of the therapy. Among proposed targets aimed at the promotion of Treg cell function, the regulation of mTOR pathway has garnered particular interest due to its preferential activation on effector T cells.3 The use of the mTOR inhibitor rapamycin in solid organ transplantation confirms a preferential differentiation and expansion of circulating Treg cells.6 mTOR inhibition is also currently being used to enhance suppressive function and stability of ex vivo–expanded Treg cells for adaptive transfer immunotherapy in kidney and liver transplantation.7 However, there is mounting evidence to propose that different Treg cell subsets exhibit distinct metabolic requirements. Different to that described on in vitro–differentiated Treg cells, a recent study performed on freshly isolated human T cells suggests that thymic-derived Treg cells are highly glycolytic and dependent on mTOR signaling.8 Therefore, greater markers to delimit the phenotypic heterogeneity of Treg cells and improved knowledge on their specific function are required to better determine the in vivo effects of metabolic reprogramming.
Furthermore, the authors include a thorough description of the different analytical methodologies designed to interrogate the metabolic signatures of immune cells. The increasing interest in the field, driven in part by recent technical developments and their wider availability, has propelled the use of immunometabolic approaches to determine novel therapeutic targets in transplantation and to identify specific metabolic patterns to be used as prognostic biomarkers. The rapid measurement of metabolic intermediates has proven to be an efficient monitoring strategy by which to assess ischemia/reperfusion injury and to detect functional alteration in the graft during acute rejection.9 In addition, mirroring achievements using transcriptional analyses,10 the assessment of tolerance-related metabolic signatures can be implemented to determine the suitability of immunosuppression withdrawal and to evaluate the efficacy of tolerogenic therapies applied in clinical transplantation. Yet, considering the reported bidirectional influence of metabolic reprogramming on gene expression and epigenetic regulation,2 the integration of metabolomic studies with transcriptional and epigenomic approaches might provide a more complete description of the functional networks mediating the allogeneic responses, and potentially unveil novel targets for combined immune manipulation.
In summary, the application of emerging metabolomic analyses in transplantation research will further elucidate the complex network of immune responses mediating allograft survival. Although therapeutic targeting of metabolic pathways is of evident promise as a strategy toward immune modulation, further research is needed to better delineate the heterogenous metabolism of T cells infiltrating grafts and to unveil the possible off-target effects of metabolic reprogramming.
1. O'Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol
2. Pearce EL, Poffenberger MC, Chang CH, et al. Fueling immunity: insights into metabolism and lymphocyte function. Science
3. Verbist KC, Guy CS, Milasta S, et al. Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature
4. Lee CF, Lo YC, Cheng CH, et al. Preventing allograft rejection by targeting immune metabolism. Cell Rep
5. Tanimine N, Turka LA, Priyadharshini B. Navigating T cell immunometabolism in transplantation. Transplantation
6. Akimova T, Kamath BM, Goebel JW, et al. Differing effects of rapamycin or calcineurin inhibitor on T-regulatory cells in pediatric liver and kidney transplant recipients. Am J Transplant
7. Safinia N, Vaikunthanathan T, Fraser H, et al. Successful expansion of functional and stable regulatory T cells for immunotherapy in liver transplantation. Oncotarget
8. Procaccini C, Carbone F, Di Silvestre D, et al. The proteomic landscape of human ex vivo regulatory and conventional T cells reveals specific metabolic requirements. Immunity
9. Bonneau E, Tétreault N, Robitaille R, et al. Metabolomics: perspectives on potential biomarkers in organ transplantation and immunosuppressant toxicity. Clin Biochem
10. Bohne F, Martinez-Llordella M, Lozano JJ, et al. Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation. J Clin Invest