n-3 PUFA-mediated CD4+ T cell Differentiation

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(Last Updated On: April 4, 2020)
Omega-3 polyunsaturated fatty acid mediated T cell differentiation
Omega-3 polyunsaturated fatty acid-mediated T cell differentiation. A) Formation of the Immunological synapse at the cellular level B) Formation of the Immunological Synapse at the biochemical level

In the previous article, I mentioned about how omega-3 polyunsaturated fatty acids (n-3 PUFA) affect the T cell signaling in which I have described n-3 PUFAs mediated T cell Receptor activation and downstream signaling. Now, I will describe how omega-3 polyunsaturated fatty acids affect T cell differentiation and some recommendations for future studies.


Activated CD4+ T cells differentiate into a subset effector cells such as TH1 and TH17 in the presence of cytokines. For example, Interferon-γ (IFN-γ) and interleukin-12 (IL-12) leads to the differentiation of the CD4+ T cells into the TH1 type of effector cells while Transforming Growth Factor-β (TGFβ), interleukin-6 and -21 (IL-6 and L-21) leads to the differentiation of the CD4+ T cells into the TH17 type of effector cells.

Different subsets of CD4+ T effector cells are defined by their transcriptional signatures, however, the plasma membrane also plays an important role in the differentiation of the CD4+ T cells. Omega-3 polyunsaturated fatty acids can alter the plasma membrane and subsequently affect the cytoskeleton-dependent signaling involved in the CD4+ T cell differentiation.

The role of lipid rafts in CD4+ T cell differentiation

CD4+ T cells treated with methyl-β-cyclodextrin found to have disrupted lipid rafts and, therefore, unable to differentiate into the TH2 cells. However, if the CD4+ T cells are treated with the 7-ketoxycholesterol, it has been found that the membrane order of the T cell is reduced that led to the T cell differentiation into the IFN-γ.

In the same way, if the level of glycosphingolipids of the T cells is decreased, it results in the reduction of the TH17 differentiation. All these results demonstrate the structural importance of the membrane orders and lipid rafts for the CD4+ T cell differentiation.

But how do Omega-3 polyunsaturated fatty acids affect T cell differentiation?

Omega-3 polyunsaturated fatty acids suppress the CD4+ T cell activation and differentiation. In the presence of omega-3 PUFAs, T cells are unable to differentiate into TH1 or TH17 cells. These differentiations are accompanied by the changes in the downstream signaling pathway such as reduced activation of the TH17 related STAT3 as well as reduced expression of the TH17 related cytokines (IL-17A) and transcription factor (RORγt). However, omega-3 PUFA does not affect the polarization of the CD4+ T cells into the TH2 or other subsets.

Fas receptor (FasR) located in the lipid raft of the CD4+ T cell interacts with the Fas Ligand and undergoes oligomerization. The oligomerization of the FasR leads to the favorable interaction between the lipid rafts that again highlights how the protein-protein interaction mediates the stabilization and organization of the lipid raft.

T cell receptor itself forms a cholesterol-dependent nanocluster in the plasma membrane that requires both cholesterol and sphingomyelin for the TCR dimerization. Therefore, the precise organization of the plasma membrane is mediated by the set of interactions such as lipid-lipid, lipid-protein and protein-protein interactions.

Using super-resolution microscopy, it can be possible to visualize the nanoclusters in the plasma membrane to determine whether the omega-3 polyunsaturated fatty acids can also affect the protein-protein interaction to form the T cell receptor clusters.

Omega-3 polyunsaturated fatty acid mediated T cell differentiation
n3-PUFA mediated T cell differentiation causes suppression of the IL-6-gp130-STAT3 signaling pathway.  A) n3-PUFA decreases the colocalization of the glycoprotein gp130 suppressing the IL-6-gp130-STAT3 signaling pathway B) n3-PUFA decreases the dimerization of glycoprotein gp130 halting the IL-6-gp130-STAT3 signaling pathway.

Further Recommendations

However, not all omega-3 polyunsaturated fatty acids are effective to stabilize the lipid rafts in the plasma membrane. Phenotypes can’t be interchanged if the T cell is treated with EPA or DHA because these omega-3 PUFAs have unequal disruption efficiency of the lipid rafts.

For example, 1-palmitoyl-2-docosahexaenoyl-phosphatidylethanolamine leads to the segregation into the non-raft plasma membrane while 1-palmitoyl-2-docosahexaenoyl phosphatidylcholine prefers the mesoscale raft domain of the plasma membrane.

These effects demonstrate that the head group of the phospholipids can also affect the mechanism by which these omega-3 polyunsaturated fatty acids modulate the plasma membrane properties

However, further study is required to elucidate how these omega-3 polyunsaturated fatty acids affect the nanoscale organization of the plasma membrane and how do they mediate the suppression of the CD4+ T cell activation and differentiation into pathological effector subsets.

Reference: European Journal of Pharmacology (Omega-3 fatty acids, lipid rafts, and T cell signaling)

Article DOI: 10.1016/j.ejphar.2015.03.091

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