Generating Immune Tolerance for the Embryo/Fetus - Hold the Sugar, Pass the Fat

Posted By Dr. Braverman || 8-Nov-2013

Recent years have seen a dramatic increase in our understanding of the crosstalk between immunology and metabolism and the emergence of the field of immunometabolism. For example, it is now well established that obesity is associated with chronic inflammation and that several immune cell types contribute to obesity-associated metabolic dysfunction, including type 2 diabetes and cardiovascular diseases.

Recent work has started to elucidate many details on how metabolism affects immune function at the cellular level. It has been known for several decades that the metabolic needs of immune cells, and T cell particularly, change considerably with the onset and development of an immune response. Resting T cells (T cells that have not yet differentiated into regulatory or cytotoxic cells) have a relatively low metabolic demand and use a balance of glucose (sugar), lipids (fat), and amino acids (protein) as their metabolic fuel. This balanced "diet" provides T cells with adequate energy in the form of ATP to support their migration through secondary lymphoid organs in their surveillance role.

Once T cells encounter foreign(this is what an embryo presents) or altered-self antigens(seen in autoimmune disease) in lymphoid organs they become activated and differentiate into one of several different lineages, including Th1, Th2, Th17, and Treg. T cells of the Th1, Th2 and Th17 lineages are broadly referred to as "effector" cells (Teff cells) as they are primarily involved in eliminating cells that are sources of the foreign or altered-self antigens through both direct and indirect means. THESE ACTIVATED T EFF CELLS ARE MOST LIKELY A SIGNIFICANT FACTOR IN EMBRYO/FETAL REJECTION. Regulatory T cells (Treg cells), on the other hand, are involved in suppressing immune responses to antigens. As we have discussed in this previous blog, Tregs play a critical role in establishing and maintaining tolerance of the maternal immune system towards an embryo/fetus that contains "foreign" paternal antigens.


Activation of T cells causes them to undergo a dramatic metabolic reprogramming. For many years it has been known that Teff cells rapidly decrease their metabolic use of lipids (lipid oxidation) and shift the way they process glucose away from oxidative phosphorylation and towards glycolysis. While this shift towards glycolysis reduces the efficiency of energy (ATP) production, it provides a rich source of biosynthetic precursors to support cell growth and proliferation.

While details about metabolic changes during activation of Teff cells have been known for many years, relatively less has been known about metabolic processes of the more newly discovered Treg cell subset. Recent work however, pioneered at Duke University and now being rapidly followed up on by scientists around the world, has now shown that Treg cells have dramatically different metabolic requirements than Teff cells. Specifically, while Teff cells rely heavily on glucose metabolism through glycolysis and shut down lipid metabolism through lipid oxidation, Treg cells conversely rely heavily on lipid oxidation, and not on glycolysis, for fuel.

The results of this and subsequent work have shown that these differences in cellular metabolism greatly affect lineage fates of T cells upon activation. Further, these distinct metabolic differences can be exploited experimentally and therapeutically to favor the generation of specific T cell lineages. In fact, this ability to alter T cell differentiation through metabolic manipulation appears to provide a mechanistic explanation for the immune modulatory effects of many existing therapeutics, including metformin and intralipids.

Metformin is a commonly used anti-diabetic drug and is also very useful in treating insulin resistance associated with PCOS. Additionally, metformin has been known for many years to have significant anti-inflammatory properties. Metformin binds to a protein in cells called AMPK and causes it to be activated. Once activated, AMPK in turn inhibits the function of another protein called mTOR that is a master regulator of cellular metabolism. It has now been shown that by inhibiting mTOR, and thus decreasing glycolysis and increasing lipid oxidation, metformin significantly favors the generation of Treg cells upon T cell activation. Thus, favoring the differentiation of Tregs appears to be a major mechanism by which metformin achieves it anti-inflammatory effects.

It has also been shown that addition of exogenous fatty acids (primary components of intralipids) to T cells during activation inhibits differentiation of Teff cells and favors differentiation of Tregs. In fact, this appears to be a likely mechanism through which intralipids achieve their immunomodulatory function. (IN FACT WE HAVE IDENTIFIED LIPID COMBINATIONS THAT WOULD WORK MUCH BETTER THAN THE 20% INTRALIPID PRODUCT THAT IS AVAILABLE IN THE US, AND WOULD DO A MUCH BETTER JOB IN INCREASING THE T REG/T EFF CELL RATIOS BUT THESE PRODUCTS ARE ONLY AVAILABLE OUTSIDE THE US). While intralipids have been used for years in women experiencing recurrent pregnancy loss with good success, a satisfactory explanation for its therapeutic effects has been largely lacking. While many clinicians point to inhibitory effects on NK cells, there is so far no satisfactory explanation for how inhibition of NK cells is achieved. In fact, Tregs have strong regulatory effects on NK cells, (that is T reg cells lower NK cell) and NK cells are present at much higher levels in mice that lack Tregs. Given the demonstrated effects of exogenous fatty acids on favoring the differentiation of Tregs, it appears very likely that the effects of intralipids on NK cells are not mediated directly, but rather indirectly through downregulation of NK cell function by Tregs induced by the intralipids. In fact, downregulation of NK cells may only be a "symptom" of the effects of intralipids' effects on Tregs and its therapeutic effects may be mediated by Tregs independent of NK cells. Further research will be needed in this area to dissect the mechanisms of immune regulation by intralipids, but it seems certain that metabolic regulation of T cell function will be central.

Immunology is one of the fastest moving fields in all of science, and it is critically important to invest significant time and effort into staying up to date with the research literature in order to have the latest knowledge for use in clinical practice. Here at Braverman IVF & Reproductive Immunology we are keeping a close eye on new research developments in the field of immunometabolism and many other fast-moving areas of immunology so that we can provide our patients with cutting-edge diagnostic and therapeutic approaches to help them achieve successful pregnancies. You can contact us today to learn more.

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