Immune defenses and their metabolic balance

When a T cell encounters its antigen (an element that the immune system can recognize as a target), it is as if it receives an alarm call: something in the body requires immediate attention. But to respond with strength and effectiveness, it needs fuel and precise instructions: this is where mTOR comes into play, the molecular complex seen previously in the insulin pathway chapter; therefore, in addition to acting as an operational hub that integrates signals from the environment, such as nutrients and growth factors, it also interacts with immunological stimuli. Among its two main complexes, mTORC1 acts as an accelerator that, once pressed, initiates the growth and transformation of naïve T cells (T lymphocytes, i.e., immune system cells that have not yet encountered the specific antigen for which they were programmed) into true soldiers – effector cells.

One of the most surprising roles of mTORC1 is to activate, even in the absence of hypoxia, the key factor HIF1α (Hypoxia-Inducible Factor 1 alpha), which was also seen previously. Normally, HIF1α is rapidly degraded when there is enough oxygen. But if mTORC1 is active, this factor is produced and stabilized anyway, as if the hypoxic environment were being “simulated.” This activation is not random: HIF1α is essential for driving a profound change in the metabolism of T cells, pushing them toward glycolysis, which is a type of cellular respiration that is very rapid but less efficient. It is like switching from a hybrid car to a turbo engine that consumes more fuel but accelerates immediately: perfect in the event of an immune emergency.

HIF1α acts on multiple fronts. On one hand, it promotes the synthesis of transporters such as GLUT1 and the activation of glycolytic enzymes, ensuring an immediate influx of energy necessary to support the proliferation and function of effector cells (Shi et al., 2011) [5]. On the other hand, it modulates their identity. T cells do not all become the same: some assume a regulatory role, maintaining balance (Tregs), while others transform into active fighters, such as Th17 cells or cytotoxic CD8⁺ lymphocytes. HIF1α strongly favors this second option. In fact, it promotes the production of a specific factor, fundamental for directing cells toward Th17 specialization, and simultaneously degrades FOXP3 (a protein fundamental for the functioning of regulatory T lymphocytes), the “trademark” of Tregs (Guan et al., 2017) [6].

This dual action has also been observed in experimental models of autoimmune disease: the lack of HIF1α in T cells reduced inflammation and increased the presence of Tregs, suggesting that blocking this factor could have important therapeutic implications (Dang et al., 2011) [7].

The link between mTOR and HIF1α, therefore, is not only biochemical but strategic. mTORC1 activates HIF1α to ensure that T cells not only receive energy rapidly but also transform into effectors capable of dealing with infections or inflammatory situations decisively. It is a closed but dynamic circuit: mTORC1 fuels HIF1α, which in turn switches on glycolysis and the transcription of factors that change the fate of the T cell, promoting aggressive and, in certain cases, even excessive immunity (Wang et al., 2024) [8].

In simple terms, we could say that mTOR is the switch, and HIF-1α is the transformer that turns on the high-performance engine of T cells, directing them to become tireless fighters rather than peacemakers. And like any powerful system, if left unchecked, it can contribute to chronic inflammation and autoimmunity. Precisely for this reason, today, mTOR and HIF-1α are also under special observation in the therapeutic field.

In the immune system, the balance between attack and tolerance is regulated by a refined system of “metabolic switches” that determine whether a cell should respond forcefully or remain silent. Two of these molecular switches are mTOR, which we discussed in depth in Chapter 4 regarding the insulin pathway, and AMPK; these are two kinases that function somewhat like the accelerator and brake of the immune system. mTOR, for example, can be imagined as a control unit that assesses whether there are enough nutrients and resources to activate the immune response. When the “traffic light” is green—that is, when glucose, amino acids, and growth factors are available—mTOR activates and promotes the growth, proliferation, and specialization of T cells into pro-inflammatory subtypes such as Th1, Th2, and Th17 (Powell and Delgoffe, 2010) [14]. This process is crucial for fighting infections or reacting to an external threat, but if it remains switched on for too long, it can fuel a chronic inflammatory response.

The activation of mTORC1 pushes T cells to switch from oxidative metabolism to a glycolytic one, similar to the “turbo engine” used by a race car: it consumes a lot, but accelerates rapidly. This strategy is ideal for cells that need to proliferate quickly, such as effector cells. However, to maintain immune homeostasis and turn off inflammation, another type of energy and another type of guidance are needed: this is where AMPK comes into play. As the other major regulator, it activates when resources are scarce, for example during fasting or metabolic stress, and promotes a more efficient metabolism based on fatty acid oxidation, which is slower but sustainable in the long term (Sun et al., 2017) [15].

In this scenario, regulatory T cells (Treg), which are responsible for “cooling down” immune reactions and maintaining tolerance, rely on more sober metabolic pathways, such as lipid oxidation, supported by AMPK. Conversely, effector cells like Th17, which are specialized in sustaining inflammation, depend on glycolysis and therefore on mTOR. This link between metabolism and immune function has also been observed in murine models (mice or rats used as models in scientific studies), where AMPK stimulation favored the generation of Treg, while mTOR activation promoted the expansion of Teff (Michalek et al., 2011) [16].

But these two regulators do not work in isolation: they interact and influence each other. AMPK can inhibit mTORC1 through the phosphorylation of TSC2, acting as an emergency brake capable of interrupting the pro-inflammatory cascade and favoring the transition toward immune tolerance (Chi, 2012) [17]. This antagonism has significant clinical implications: for example, mTOR hyperactivity has been associated with autoimmune and chronic inflammatory diseases, where the immune response becomes excessive and uncontrolled. This is why drugs like rapamycin, an mTOR inhibitor, are used as immunosuppressants (Waickman and Powell, 2012) [18].

However, one must also consider the other side of the coin. While AMPK helps contain inflammation, excessive activation of this system could compromise the immune response necessary to fight infections or tumors. Like an overly cautious commander, AMPK could prevent immune troops from intervening with force when it is truly needed (Wang et al., 2019) [19].

In oncology, for example, it has been observed that mTOR plays a crucial role in enhancing the response of T lymphocytes against tumor cells. Inhibiting mTOR indiscriminately could therefore hinder the effectiveness of immunotherapy. Consequently, the clinical challenge is to find the right balance: modulating mTOR and AMPK in a personalized way, as if adjusting the volume between two speakers, to obtain an immune response that is strong but controlled, effective but safe (Gerriets and Rathmell, 2012) [20].

In summary, mTOR and AMPK represent the two sides of the same immune coin. The former pushes the system to react, the latter invites it to calm down. And as in any good control system, health depends on the ability to switch from one state to the other with the right timing and according to the body's actual needs.

When we talk about new therapeutic strategies to address inflammatory and autoimmune diseases, the biochemical dialogue between mTOR and AMPK emerges as a crucial point. We have seen how mTOR acts as an accelerator for the immune system, while AMPK acts as a brake: the former pushes the inflammatory response forward, while the latter balances it and, when necessary, slows it down. This finely orchestrated dynamic represents a valuable opportunity to intervene in the immune system in a targeted manner.

An emblematic example is the use of rapamycin, a specific mTOR inhibitor, which has shown a direct and selective effect on regulatory T cells (Tregs). In a pioneering study, it was demonstrated that rapamycin is capable of expanding CD4+ CD25+ FoxP3+ T cells in vitro without compromising their suppressive function. This result opened the door to the possibility of using the drug in ex vivo cell therapies (with reinfusion into the patient) to enhance immune tolerance in patients suffering from autoimmune diseases or in transplant settings (Battaglia et al., 2005) [24].

Confirming this, another study observed how rapamycin improves the clinical course of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. This improvement was achieved through dual modulation: on one hand, a reduction in pro-inflammatory effector T cells, and on the other, an expansion of Tregs, with a favorable balance in the ratio between these two cell populations (Esposito et al., 2010) [25].

However, the strategy is not limited to mTOR inhibition. One can also act on the opposite side by boosting AMPK, which represents a sort of "anti-inflammatory switch." Natural substances and synthetic compounds are emerging as AMPK stimulators, capable of steering the immune system toward a more regulated and less aggressive response.

For example, arctigenin, a natural compound derived from the seeds of Arctium lappa, has demonstrated effective anti-inflammatory action in macrophages: it not only reduces inflammatory cytokines such as IL-1β, IL-6, and TNF-α, but also promotes polarization toward an anti-inflammatory M2 phenotype through the inhibition of the PI3K/AKT pathway (Hyam et al., 2013) [26].

In parallel, LZ205, a newly synthesized flavonoid (a natural plant-derived substance belonging to the polyphenols), has been shown to block the polarization of M1 macrophages—the pro-inflammatory ones—again through the suppression of the PI3K/AKT/mTOR cascade, resulting in a reduction of inflammation in both colitis and peritonitis models (Bai et al., 2018) [27].

Taken together, these results tell us that it is possible to intervene in the immune system either by pressing the brake (activating AMPK) or by taking the foot off the accelerator (inhibiting mTOR). From a therapeutic perspective, the combination or targeted selection of these strategies could represent a new frontier for the treatment of immune-mediated diseases, offering personalized approaches that take into account the patient's metabolic and immunological status.

When discussing immune tolerance and the regulation of the inflammatory response, the transcription factor Foxp3 represents a sort of “molecular signature” of regulatory T cells, or Tregs. Much like a conductor leading an entire symphony, Foxp3 regulates the genes responsible for the suppressive function of these cells, maintaining the balance of the immune system. Its expression is not merely a simple marker, but an essential requirement to confer identity and functional capacity upon Tregs. When Foxp3 is absent or altered, Tregs lose their control over immune responses, and severe autoimmune diseases can develop, as demonstrated in patients affected by IPEX syndrome, which is linked to mutations in the FOXP3 gene (Bacchetta et al., 2007) [28].

CD4+ CD25+ Treg cells, produced primarily in the thymus, play a central role in preventing the immune system from attacking the body’s own tissues. Foxp3 acts actively within these cells, blocking genes that stimulate inflammation and activating those that promote tolerance. If we think of the immune system as a security system, Foxp3 is the “central regulator” that prevents false alarms: it prevents the body from reacting against its own tissues in an excessive or incorrect manner (Sakaguchi et al., 2006) [29].

The metabolic environment in which these cells operate profoundly influences the stability and effectiveness of their function. The mTOR pathway, activated by an abundance of nutrients and growth signals, tends to promote the proliferation of effector T cells and can interfere with the stability of the Treg phenotype. Conversely, the activation of AMPK, a cellular sensor activated by fasting, exercise, or energy stress, creates a metabolic context favorable to Foxp3 function, promoting a more acceptable and less inflammatory response. In simple terms, we could say that AMPK “nourishes” calm and immune balance, while mTOR can fuel the activation and aggressiveness of responses (Bacchetta et al., 2007) [28].

Diet also plays an important role: dietary regimens rich in calories and nutrients, which strongly stimulate mTOR, appear to reduce the expression and stability of Foxp3, favoring an imbalance that can facilitate the development of inflammatory diseases. Conversely, caloric restriction or nutritional approaches that stimulate AMPK can increase Foxp3 expression, thereby strengthening the ability of Tregs to maintain immune homeostasis (Sakaguchi et al., 2006) [29].

This type of approach could revolutionize the management of autoimmune pathologies, where the deficiency or dysfunction of Tregs is one of the primary causes of the disease. Enhancing the Foxp3 pathway, whether through metabolic strategies (such as diet or AMPK activation) or with immunomodulatory drugs (such as rapamycin), represents a concrete opportunity to restore immunological balance and contain the aggressiveness of autoimmune responses. In other words, supporting the action of Foxp3 in Tregs is equivalent to strengthening the “natural brake” of the immune system, helping it distinguish between what should be defended and what should be tolerated.

Vitamin D, in its active form called calcitriol (1,25(OH)₂D₃), acts almost like a conductor for the immune system. T lymphocytes, including regulatory T cells (Tregs), possess a specific receptor for this vitamin, known as the VDR (Vitamin D Receptor). When calcitriol binds to this receptor, it triggers a signaling cascade that leads to the modulation of the expression of hundreds of genes, many of which are directly involved in the balance between tolerance and inflammation. It is as if vitamin D can, in part, decide whether the immune orchestra should play a calm and harmonious symphony or unleash an inflammatory assault.

One of the most significant effects of calcitriol is its ability to direct naïve T cells toward a regulatory fate, transforming them into Tregs rather than pro-inflammatory effector cells such as Th1 or Th17. This orientation occurs mainly through two mechanisms: the first is the increased expression of the transcription factor FOXP3, the true hallmark of Tregs. Clinical studies have shown that vitamin D administration directly promotes the production of FOXP3, strengthening the suppressive capabilities of Tregs and the maintenance of immune homeostasis (Terrier et al., 2012) [36].

The second mechanism concerns dendritic cells, which act as a sort of "teacher" for immature T cells. In the presence of vitamin D, these cells adopt a more orderly behavior, meaning they are less prone to stimulating inflammation, thereby facilitating the transformation of T cells into regulatory cells rather than inflammatory effectors (Hafkamp et al., 2022) [37].

This dual effect produces a clear shift in the immune balance: from a pro-inflammatory state dominated by Th1 and Th17 cells, which are responsible for autoimmune diseases such as systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis, to a state of immunological tolerance. In patients with lupus, for example, vitamin D supplementation has led to a clear reduction in Th1 and Th17 cells, accompanied by an increase in Tregs and a drop in anti-DNA autoantibodies, which are typical markers of the disease (Terrier et al., 2012) [36].

The same trend has also been observed in preterm infants, a population notoriously vulnerable to immune imbalances. In a randomized controlled trial, daily supplementation of 800 IU of vitamin D3 resulted in an increase of up to 73% in Tregs, compared to a modest 1.8% in the group receiving 400 IU (Aly et al., 2019) [38]. These data suggest not only the efficacy of vitamin D in promoting more stable immune regulation but also a clear dose-dependent effect.

In summary, vitamin D can be considered a true therapeutic lever for reorienting the immune system. Through the induction of FOXP3 and the promotion of more tolerant dendritic cells, it favors the expansion and function of Tregs, shifting the immune balance toward calm and tolerance, rather than inflammatory aggression. A simple intervention like supplementation can therefore have profound effects, both in the prevention and management of autoimmune and inflammatory diseases.

Throughout the previous chapters, a pathophysiological reality as simple as it is disruptive has strongly emerged: glycemic variability is the terrain upon which every systemic balance either flourishes or breaks down. The silent and constant director is not just the absolute value of glycemia, but precisely its variability—that is, how much blood glucose levels fluctuate throughout meals, the day, and the years. Long overlooked, postprandial glycemic variability (glycemia within 1/2/3 hours after a meal) is now emerging as the primary sign of dysfunction, long before fasting glycemia or HbA1c levels appear altered.

Downstream of these fluctuations, a chronic and insidious condition inevitably develops: compensatory hyperinsulinemia. This is not yet full-blown insulin resistance or diabetes, but a constant insulin hyper-stimulus, necessary to contain the glycemic spikes generated by an inadequate and unproductive lifestyle. This chronic excess of insulin represents the central link in metabolic maladaptation, activating deeply conserved intracellular pathways (a set of mechanisms and biochemical pathways that have remained almost unchanged throughout evolution) that are sensitive to energy availability.

Among these, as we have already seen in previous chapters, the mTOR (mechanistic Target of Rapamycin) complex plays a crucial role: it acts as a sensor and regulator of cell growth, responding to the presence of nutrients, insulin, and growth factors. Under physiological conditions, mTOR orchestrates proliferation, repair, and anabolism. But in the presence of chronic hyperinsulinemia and altered metabolic signals, mTOR can become excessively activated, contributing to inflammatory states, immune dysregulation, and autoimmunity.

Why is all this important in the context of the immune system?

To understand autoimmune or chronic inflammatory diseases, such as rheumatoid arthritis, psoriasis, inflammatory bowel diseases, etc., it is essential to start from what happens within the insulin pathway, whose main actor is mTOR itself. We are no longer dealing with an immune system that has "gone crazy" at random, but with a context in which disturbed energy signaling alters immune homeostasis, modulating: M1 and M2 (the two main functional states of macrophages), the polarization of T eff and T reg lymphocytes (the two subgroups of T lymphocytes), the chronic activation of innate immune cells (the body's first line of defense, active from birth), the persistent production of pro-inflammatory cytokines that activate the immune response, and, finally, immunological exhaustion and the loss of tolerance.

In the next chapter, we will address some of the main pathologies of the immune system, conditions that represent not only a defense dysfunction but the result of a complex interplay between metabolism and daily habits. The immune system, in fact, does not live in isolation: it constantly communicates with hormones, nutrients, and signals coming from our lifestyle. Every dietary choice, every glycemic fluctuation, and every environmental factor contributes to modulating its strength or compromising its balance.

Every pathology we will address in the following paragraphs will have its own specificity, genetics, and organ target, but all of them, without exception, will be observed with a new perspective: one that starts from the new frontier defined as "immunometabolism." This will allow us not only to explain the origin of symptoms and organ damage more coherently but also to identify concrete intervention strategies based on the modulation of insulin, mTOR, and the nutritional stimuli that influence them.