Editorial on the Research Topic
Immunometabolic Regulations in Adaptive and Innate Immune Cells Shapes and Re-Directs
Host Immunity
Metabolism
Metabolism, a nightmare for many students and, let’s be honest, not-anymore students
alike. Complicated pathways and crosstalks between metabolites and metabolic enzymes—with
little tangible relation to any real-life biology. In the past two decades, however,
very concrete clinical scenarios, such as cancer, diabetes, and immunity, have become
inseparably tied to cellular metabolic dysregulation. With unprecedented breath and
depth new technologies, such as metabolomics, proteomics, RNA-sequencing, and epigenomics,
allowed interrogating cellular metabolism, its links to organismal metabolic changes,
as well as its regulation and biologic importance in health and disease.
In this research topic, which entails 11 invited review articles, we are focusing
on how metabolic regulation fine-tunes activation, differentiation and acquisition
of effector function among both innate and adaptive immune cells.
Starting out, a review by Wei et al. provides an overview on how regulatory circuits
of oxygen- and nutrient-sensing machineries orchestrate T cell responses. The authors
further discuss the role of autophagy and the redox- and NAD+/NADH balance in T cell
differentiation and activation. A review article by Gardiner and Finlay discusses
the uniqueness of metabolic regulation in guiding NK cell activation and NK cell dependent
immune responses. The work by Langston et al. covers, in detail, mechanisms by which
distinct signals induce a metabolic shift in macrophages, and how such metabolic adaptation
sustains signaling pathways to drive macrophage polarization. The authors further
discuss how metabolic regulation in macrophages centers on mitochondria to enforce
cell activation. The review by Sancho et al. discusses how mitochondrial activity,
and in particular the dynamics of the electron transport chain, acts as a rheostat
to modulate signaling, transcription, and the epigenome of innate immune cells. Chao
et al. go on to discuss how mitochondria regulate T cell activation, differentiation,
and function. The authors of this paper further highlight how mitochondrial fitness
and dynamics relate to T cell immunity in cancer, infection, autoimmunity, and during
aging.
The review by Binger et al. is focused on metabolic reprogramming in CD4+ helper T
cells, with a particular emphasis on Th17 and regulatory T cells (Tregs). The article
highlights the metabolic demands of Th17 cells, and describes how metabolic regulation
in Th17 cells contributes to autoimmunity. Kolev and Kemper then discuss the role
of complement, an emerging player of immunometabolic regulation. The authors postulate
that this ancient arm of the immune system may indeed have coevolved with immunometabolism.
The last four papers of this research topic emphasize contributions of immunometabolic
regulation in cancer, atherosclerosis, and obesity. First, Renner et al. discuss metabolic
communication and competition between immune- and cancer-cells in the tumor microenvironment
and propose therapeutic strategies to enhance anti-tumor immunity by augmenting metabolic
fitness of tumor-infiltrating immune cells. Patsoukis et al. highlight how co-inhibitory
receptors tailor metabolic reprogramming and pathway usage in T cell subsets. Since
tumor-infiltrating T cells often express co-inhibitory receptors, understanding the
metabolic circuits controlled by these receptors may provide a springboard toward
reinvigorating cancer-directed T cell immune responses via metabolic reprogramming.
Based on the idea that tumor-infiltrating T cells may face a metabolic crisis in the
tumor microenvironment, Irving et al. discuss how metabolic rewiring may be an attractive
strategy for designing new T cell-based cancer immunotherapies, particularly chimeric
antigen receptor T cell therapies. In addition to T cells, Geeraerts et al. describe
how the metabolic environment in tumors and in atheromatous lesions affects macrophage
polarization and function via intervening with cellular metabolic processes. This
article further discusses how altered systemic metabolism among obese individuals,
and mice, may promote metabolic disorders, including insulin resistance, by modulating
inflammatory properties of adipose tissue macrophages.
In summary, this research topic highlights the tremendous progress that has been made
in understanding how metabolic reprogramming underpins immune cell differentiation,
activation, and effector function. However, and as also highlighted by the various
contributions, key questions regarding the detailed molecular mechanisms by which
metabolic pathways control immune cell responses are still unresolved. Specifically,
important metabolic checkpoints remain to be described, and it is still an enigma
how metabolic checkpoints crosstalk to orchestrate immune responses. We hope that
this research topic not only will serve as a valuable resource but also that it will
also provoke questions and help formulating relevant next-generation research questions—with
the ultimate goal to exploit immunometabolic regulation to the benefit of patients.
Author Contributions
All authors listed have made a substantial, direct, and intellectual contribution
to the work and approved it for publication.
Conflict of Interest Statement
These authors declare no financial relationship that can cause conflict of interest
with the contents of this work.