Targeting Metabolic Pathways to Tune Immune Cells

Targeting Metabolic Pathways to Tune Immune Cells

Learn more about some of the immune cell populations that we are studying here at Rheos. Each population has distinct function and relies on different metabolic pathways to direct and maintain function. The pathways are represented on a “map” of central cellular metabolism to illustrate the different pathways used by different immune cell types.

Click to explore:

 

M1 Macrophage

Immune Cell Type:

Pro-inflammatory macrophage

Function:

Initiates and maintains inflammation

MECHANISM:

Secretes pro-inflammatory cytokines IL-1-β, TNF, IL-12, IL-18, and IL-23

Key metabolic pathways:

Citric acid cycle and urea cycle. Utilizes pyruvate and urea to maintain function. Urea cycle contributes to the production of nitric oxide

RELEVANT PUBLICATIONS:

  • Jha AK, Huang SC, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E, Chmielewski K, Stewart KM, Ashall J, Everts B, Pearce EJ, Driggers EM, Artyomov MN. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity. 2015 Mar 17;42(3):419-30.
M2 Macrophage

Immune Cell Type:

Anti-inflammatory macrophage

Function:

Attenuates inflammation

MECHANISM:

Secretes anti-inflammatory cytokines IL-10 and TGF-β

Key metabolic pathways:

Fatty acid oxidation

RELEVANT PUBLICATIONS:

  • Huang SC, Everts B, Ivanova Y, O’Sullivan D, Nascimento M, Smith AM, Beatty W, Love-Gregory L, Lam WY, O’Neill CM, Yan C, Du H, Abumrad NA, Urban JF Jr, Artyomov MN, Pearce EL, Pearce EJ. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol. 2014 Sep;15(9):846-55.
Effector CD8+ T Cell

Immune Cell Type:

Pro-inflammatory effector CD8+ T cell

Function:

Kills cells infected with intracellular pathogens or tumor cells

MECHANISM:

Secretes cytokines like TNF-a and IFN-g. Direct cell lysis through upregulation of perforin and granzyme

Key metabolic pathways:

Glycolysis. Relies heavily on sugar to maintain function

RELEVANT PUBLICATIONS:

  • van der Windt GJW, O’Sullivan D, Everts B, Ching-Cheng Huang S, Buck MD, Curtis JD, Chang CH, Smith AM, Ai T, Faubert B,. Jones RG, Pearce EJ, Pearce EL. CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. PNAS 2013 August, 110 (35) 14336-14341.
  • Phan AT, Doedens AL, Palazon A, Tyrakis PA, Cheung KP, Johnson RS, Goldrath AW. Constitutive glycolytic metabolism supports CD8+ T cell effector memory differentiation during Viral Infection. Immunity. 2016 Nov 15;45(5):1024-1037.
TH17 Cell

Immune Cell Type:

Pro-inflammatory effector CD4+ T cell

Function:

Boosts immune response by recruiting effector cells such as neutrophils and macrophages

MECHANISM:

Secretes cytokines like IL-17 and IL-21, as well as many others

Key metabolic pathways:

Glycolysis and citric acid cycle. Generally uses sugar and pyruvate to maintain function.

RELEVANT PUBLICATIONS:

  • Michalek, R.D. et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186, 3299-3303 (2011).
Treg Cell (regulatory t cell)

Immune Cell Type:

Immunosuppressive CD4+ T cell

Function:

Attenuates immune response by down-regulating effector T cells

MECHANISM:

Secrete inhibitory cytokines like TGF-β, IL-35, and IL-10

Key metabolic pathways:

Fatty acid oxidation

RELEVANT PUBLICATIONS:

  • Gerriets VA, Kishton RJ, Johnson MO, Cohen S, Siska PJ, Nichols AG, Warmoes MO, de Cubas AA, MacIver NJ, Locasale JW, Turka LA, Wells AD, and Rathmell JC. Foxp3 and TLR signals balance Treg metabolism for proliferation or suppressive function. Nat Immunol 17:1459-66, 2016.
  • Huynh A, DuPage M, Priyadharshini B, Sage PT, Quiros J, Borges CM, Townamchai N, Gerriets VA, Rathmell JC, Sharpe AH, Bluestone JA, and Turka LA. Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat Immunol 16:188-96, 2015.
  • Michalek, R.D. et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186, 3299-3303 (2011).
Memory CD8+ T Cell

Immune Cell Type:

Long-lived T cell that has previously been
exposed to an antigen

Function:

Adaptive immunity

MECHANISM:

Rapid expansion to large numbers of effector T cells upon re-exposure

Key metabolic pathways:

Fatty acid oxidation

RELEVANT PUBLICATIONS:

  • Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, Jones RG, Choi Y. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature. 2009 Jul 2;460(7251):103-7.
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