The immune system possesses a remarkable capacity for memory, traditionally linked to adaptive immunity. However, a newer understanding reveals that even innate immune cells, the body’s first line of defense, can develop a form of “memory” through a process called trained immunity. This phenomenon involves long-term functional modifications in these cells, leading to a heightened response upon subsequent encounters with various stimuli. This area of immunology is expanding our comprehension of how the immune system defends against threats.
A New View of Immunity
Traditionally, the immune system has been divided into two main branches: innate and adaptive immunity. Innate immunity provides an immediate, non-specific defense against a wide range of pathogens, acting as the body’s first responder. Its cells, such as macrophages and neutrophils, recognize general patterns associated with microbes and launch a rapid attack without prior exposure. Adaptive immunity, on the other hand, is known for its specificity and memory, involving B and T lymphocytes that learn to recognize particular pathogens and mount a stronger, faster response upon re-exposure.
Trained immunity challenges the belief that only adaptive immunity possesses memory. It demonstrates that innate immune cells, despite their non-specific nature, can undergo lasting changes after an initial exposure. These changes allow them to respond more robustly to subsequent challenges, even if those challenges are unrelated to the initial stimulus. This enhanced responsiveness is not based on recognizing specific antigens, but rather on a generalized state of heightened alert. Trained immunity memory generally provides protection for a shorter duration compared to adaptive memory, ranging from approximately three months to one year.
The Mechanisms Behind Training
Trained immunity stems from fundamental changes within innate immune cells. Following an initial stimulus, such as an infection or vaccination, cells like monocytes and macrophages undergo epigenetic reprogramming. This involves modifications to how genes are expressed without altering the underlying DNA sequence. These epigenetic changes, including alterations in chromatin accessibility, DNA methylation, or histone modifications, make certain genes more readily available for transcription, leading to a more potent and rapid response to new stimuli.
Metabolic rewiring also contributes to trained immunity. Cells adjust their energy production and utilization pathways, providing the necessary energy and building blocks for enhanced inflammatory and antimicrobial responses. The combination of these epigenetic and metabolic alterations leads to a heightened, non-specific inflammatory and antimicrobial response to subsequent infections or stimuli, even those unrelated to the initial training event. This training can occur in circulating monocytes and tissue macrophages (peripheral trained immunity), and in hematopoietic stem cells in the bone marrow (central trained immunity), which can explain longer-lasting effects.
Impact on Health and Medicine
Trained immunity influences our susceptibility to various infections and offers new avenues for therapeutic strategies. Certain live vaccines, such as the Bacillus Calmette-Guérin (BCG) vaccine used against tuberculosis, provide broader protective effects beyond their specific target. This non-specific protection against unrelated infections, including viral diseases, is attributed to their ability to induce trained immunity, suggesting a potential for leveraging existing vaccines to enhance general immune resilience.
Trained immunity also plays a role in chronic inflammatory diseases. While beneficial in fighting infections, inappropriate or persistent induction of trained immunity by endogenous stimuli can contribute to aberrant inflammation. This “over-training” might exacerbate conditions like atherosclerosis, where chronic inflammation is a driving factor, or contribute to autoimmune disorders. Understanding this dual nature is important for developing targeted interventions.
Insights from trained immunity open doors for novel therapeutic approaches. By intentionally inducing or modulating trained immunity, scientists might develop strategies to boost immune responses against infections, particularly in vulnerable populations. Conversely, where trained immunity contributes to disease, therapies could aim to dampen or reverse the “trained” state of immune cells to reduce inflammation. This field holds promise for enhancing global health by optimizing immune responses against a wide array of diseases.