Getting Started in Immunometabolism – Literature Resources for Adaptive Immunity

Lymphocytes – An Army Marches on Its Metabolism

Lymphocytes migrate between wildly different microenvironments in vivo. Metabolic pathways, integrating cell-specific and site-specific factors, are intimately tied to activation, proliferation, and differentiation of lymphocytes. A circulating naïve lymphocyte may use Oxidative Phosphorylation (OxPhos) for energy, but it is non-proliferative. Blasting lymphocytes utilize glycolysis to meet high demands for metabolites for building biomass. Memory lymphocytes, often in low oxygen niches, favor glycolysis. Competition with other lymphocytes, tumor cells and microbes as well as the physiology of local nutrient and oxygen are environmental influences. Importantly, key control molecules in lymphocyte activation, such as mTOR, HIF, and NF-kappa B, are exquisitely sensitive to pericellular oxygen. As Immunometabolism coalesces as a new field, it brings a picture of comprehensive metabolic control of immunity. Here are a few recent review papers and other literature to get you started in this new field.

T Cell Activation, Proliferation, and Differentiation is Tied to Metabolism

• T cell metabolism is intimately tied to activation and proliferation through multiple signaling pathways including Notch/PI3K/mTOR (reviewed in [1] [2])

• mTORC1 and 2 differentially regulate anabolic and catabolic pathways in response to O2 changes and mTORC1 induces HIF-1a production [2]

• NF-kappa B, central to cytokine signals like TNF, is affected by O2 levels [3]

 

T Cell Phenotype and Function is Shifted by mTOR, HIF-1a and Oxygen

• Low O2 and stabilization of HIF-1 favors differentiation of Th9, Th17, and Th22 phenotypes over Th1 and Treg (reviewed in [2] [4]) [5]

• Foxp3 upregulates OxPhos and downregulates glycolytic enzymes [6]

• HIF and mTOR activity are needed for CTL effector function [7]

• Lymphnode O2 (5%) rather than 21% increased IL-10, 4-1BB and CD25 in CTL [8]

 

B Cells, the Germinal Center, and Tolerance are Affected by a Metabolic Milieu

• B cells proliferating in the GC light zone are hypoxic (reviewed in [9] [10])

• B cells cultured in low O2 exhibit reduced proliferation, AID expression, and CSR to IgG1, but not IgA, which may accommodate microbial competition for GI O2 [10]

• HIF stabilization induces CXCR4 expression, affecting B cell homing [9]

• Mice with HIF1a-deficient T and B cells exhibit increased autoimmunity [11]

• Low O2 promotes T follicular regulatory cell differentiation and these cells in turn, help limit proliferation of autoreactive GC B cells [12].

 

Appropriate In Vitro Oxygen is Critical for Immune Cell Studies

• Room air oxygen dramatically reduces HSC isolation yields [13] and increased intracellular ROS affect HSC generation and differentiation [14] [15]

• Culture under physiologic oxygen in vitro reduces T cell proliferation [4] [16]

 

References:

1. Loftus, R.M. and D.K. Finlay, Immunometabolism: Cellular Metabolism Turns Immune Regulator. J Biol Chem, 2016. 291(1): p. 1-10.

2. MacIver, N.J., R.D. Michalek, and J.C. Rathmell, Metabolic regulation of T lymphocytes. Annu Rev Immunol, 2013. 31: p. 259-83.

3. Eltzschig, H.K. and P. Carmeliet, Hypoxia and inflammation. N Engl J Med, 2011. 364(7): p. 656-65.

4. Zenewicz, L.A., Oxygen Levels and Immunological Studies. Frontiers in Immunology, 2017. 8(324).

5. Feldhoff, L.M., et al., IL-1beta induced HIF-1alpha inhibits the differentiation of human FOXP3+ T cells. Sci Rep, 2017. 7(1): p. 465.

6. Angelin, A., et al., Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments. Cell Metabolism.

7. Finlay, D.K., et al., PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J Exp Med, 2012. 209(13): p. 2441-53.

8. Vuillefroy de Silly, R., et al., Phenotypic switch of CD8+ T cells reactivated under hypoxia toward IL‐10 secreting, poorly proliferative effector cells. European journal of immunology, 2015.

9. Burrows, N. and P.H. Maxwell, Hypoxia and B cells. Exp Cell Res, 2017.

10. Cho, S.H., et al., Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system. Nature, 2016. 537(7619): p. 234-238.

11. Kojima, H., et al., Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1α-deficient chimeric mice. Proceedings of the National Academy of Sciences, 2002. 99(4): p. 2170-2174.

12. Abbott, R.K., et al., The GS Protein-coupled A2a Adenosine Receptor Controls T Cell Help in the Germinal Center. J Biol Chem, 2017. 292(4): p. 1211-1217.

13. Mantel, C.R., et al., Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock. Cell, 2015. 161(7): p. 1553-65.

14. Ludin, A., et al., Reactive oxygen species regulate hematopoietic stem cell self-renewal, migration and development, as well as their bone marrow microenvironment. Antioxidants & redox signaling, 2014. 21(11): p. 1605-1619.

15. Ronn, R.E., et al., Reactive Oxygen Species Impair the Function of CD90+ Hematopoietic Progenitors Generated from Human Pluripotent Stem Cells. Stem Cells, 2017. 35(1): p. 197-206.

16. Vuillefroy de Silly, R., P.Y. Dietrich, and P.R. Walker, Hypoxia and antitumor CD8+ T cells: An incompatible alliance? Oncoimmunology, 2016. 5(12): p. e1232236.