Harnessing epigenetic reprogramming to engineer our body's defenses against infections, chronic diseases, and cancer
For decades, immunology textbooks drew a clear line: our immune defense came in two parts. The adaptive immune system, with its T and B cells, was the sophisticated learner, able to remember past infections and provide long-lasting protection. The innate immune system, in contrast, was considered the primitive, non-specific first responder—effective but lacking any memory.
This fundamental understanding was upended in 2011 when a groundbreaking new concept was introduced: trained immunity1 .
Scientists discovered that our innate immune cells—macrophages, monocytes, and others—are not the simple foot soldiers we once believed. Through a process of epigenetic and metabolic reprogramming, these cells can indeed be "trained" by an initial exposure to mount a dramatically stronger, faster response upon encountering a second threat, even if that threat is completely unrelated to the first1 .
Alterations to DNA accessibility that don't change the genetic code but affect gene expression.
Shifts in cellular energy production to support enhanced immune function.
Innate immune cells develop enhanced responsiveness after initial exposure.
Trained immunity is not about generating targeted antibodies, as the adaptive system does. Instead, it fundamentally rewires the inner workings of innate immune cells.
When an innate immune cell encounters a training stimulus—such as a vaccine like BCG (for tuberculosis) or a component of the fungal cell wall called β-glucan—it undergoes profound internal changes. Its metabolism shifts to rely more heavily on glycolysis, providing rapid energy and building blocks. Simultaneously, epigenetic markers on its DNA are altered, effectively "unlocking" genes responsible for a powerful inflammatory response1 . When this cell or its descendants encounter another challenge, these pre-activated pathways allow it to spring into action with unprecedented speed and force.
Bioengineers are particularly interested in two different training arenas1 :
Occurs in the bone marrow, where long-lived hematopoietic stem cells (HSCs) are reprogrammed. This creates a sustained source of trained innate immune cells that circulate throughout the body for months or even longer.
Takes place in mature, tissue-resident cells like skin macrophages or liver Kupffer cells. This provides a potent, but more localized and shorter-lived, state of alert.
The challenge and opportunity for bioengineering lie in learning how to selectively activate one type of training over the other, tailoring the immune response to the specific threat at hand1 .
To understand how bioengineers are manipulating immune cells, let's examine a key experiment that uncovered the role of a long non-coding RNA called MIAT in shaping the immune response2 .
T helper 17 (Th17) cells are essential for fighting fungal and bacterial infections, but when improperly regulated, they can drive autoimmune diseases like rheumatoid arthritis and multiple sclerosis2 .
CD4+ T cells were isolated from human umbilical cord blood. These naive cells were then cultured under specific conditions designed to push them toward becoming Th17 cells, using a cocktail of cytokines (IL-6, IL-1β, and TGFβ) and neutralizing antibodies2 .
To test MIAT's function, researchers used Locked Nucleic Acid Antisense Oligonucleotides (LNAs) to deplete MIAT from the differentiating T cells. A control group was treated with a non-targeting LNA2 .
After 72 hours of differentiation, the scientists used multiple techniques to assess the impact of MIAT loss2 :
The results were striking. The cells with depleted MIAT showed a significant reduction in the classic hallmarks of Th17 cells. The tables below summarize the core findings:
| Gene | Function in Th17 Cells | Change in Expression |
|---|---|---|
| IL17A | Master inflammatory cytokine | Decreased |
| IL17F | Inflammatory cytokine | Decreased |
| CCR6 | Chemokine receptor for homing | Decreased |
| CXCL13 | Chemokine for B cell recruitment | Decreased |
| PRKCA (PKCα) | Signaling kinase upstream of IL-17 | Decreased |
| Technique | What It Measured | Key Insight |
|---|---|---|
| LNA Transfection | Gene silencing efficiency | Successfully depleted MIAT RNA levels in human T cells. |
| RNA-seq | Global gene expression | Identified a network of Th17-related genes controlled by MIAT. |
| ATAC-seq | Chromatin accessibility | Revealed that MIAT regulates genes by altering the epigenetic landscape. |
The analysis revealed that MIAT is not a passive bystander but a critical positive regulator of human Th17 differentiation. It controls the expression of central genes, at least in part, by increasing the chromatin accessibility at key genomic loci, such as the IL17A promoter2 . This experiment provides a powerful example of how identifying a single key regulator like MIAT opens the door to new bioengineering strategies. By designing therapies to target MIAT, we could potentially "dial down" the pathogenic activity of Th17 cells in autoimmune patients without completely crippling their anti-fungal defenses.
The MIAT experiment relied on a set of sophisticated tools. The table below details some of the key "research reagent solutions" essential for this kind of cutting-edge cellular bioengineering.
| Research Reagent | Function in the Experiment |
|---|---|
| Locked Nucleic Acids (LNAs) | Synthetic nucleic acid analogs that bind to and silence target RNA (like MIAT) with high stability and affinity. |
| Cytokine Cocktail (IL-6, IL-1β, TGFβ) | A defined set of signaling proteins used to direct naive T cells to differentiate into the Th17 lineage. |
| Neutralizing Antibodies (anti-IFNγ, anti-IL4) | Antibodies that block other signaling pathways, ensuring the T cells develop into Th17 and not other T helper subtypes. |
| Anti-CD3/CD28 Antibodies | Used to artificially activate the T-cell receptor, mimicking the signal usually provided by an antigen-presenting cell. |
Precise modification of immune cell genomes using CRISPR-Cas9 and other technologies.
Advanced in vitro models for studying immune cell behavior and responses.
Genomics, transcriptomics, and proteomics for comprehensive immune profiling.
The journey to harness trained immunity is just beginning. Bioengineers are now developing even more precise tools to steer the immune system. The field is moving toward nanoparticle-based delivery systems that can carry training stimuli directly to specific organs or even bone marrow progenitor cells, offering unprecedented control over the type and location of immune training1 . Furthermore, machine learning models are being deployed to sift through vast biomedical datasets, identifying new drug targets and predicting the training potential of countless molecules in silico before they are ever tested in a lab1 .
A single nanoparticle injection provides protection against a season's respiratory viruses.
Patients with chronic inflammatory diseases receive therapies that reset their maladaptive central training in the bone marrow.
Engineered like today's CAR-T cells, these would patrol the body to seek and destroy cancerous tumors.
Machine learning algorithms design personalized immune training regimens based on individual genetic and epigenetic profiles.
The era of bioengineered trained immunity promises a future where we no longer merely respond to disease but actively reprogram our body's innate defenses to build a more resilient foundation for human health.