Natural Selection, From Within: How Immune Cells ‘Evolve’ to Defend Without Destroying

Everyday, the immune system walks a razor’s edge between life-saving protection and catastrophic self-destruction. Immune cells expertly identify and eliminate countless foreign invaders while sparing the body’s own cells from harm. This seemingly small-scale process actually parallels a much larger phenomenon that we all can recognise on the macroscale.

We usually view natural selection as a process of Darwinian evolution at the organismal level: populations adapt to be more suited to their environmental niche over generations. But within us, 'evolution' can be seen at a cellular scale, everyday. The immune system uses the same ingredients of variation and selection to sculpt a population of B and T cells to recognise virtually any foreign invader while sparing the body's own tissues.

To pull this off, immune cells undergo a series of genetic mutation and recombination events that create genetic diversity among immune cells. This variation allows several selection processes to act and eliminate dangerous or useless variants. This results in a balance between the competing forces of selecting immune cells that have a strong binding affinity to cells and selecting immune cells that are not strong enough to attack our own organs.  Consequently, devastating autoimmune conditions where the immune system mistakenly attacks 'self' cells are averted, most of the time.

In this article, we’ll explore how variation arises through V(D)J recombination and somatic hypermutation, providing the base for the next step: selection, which ensures self-tolerance through central and peripheral tolerance (with a nod to the 2025 Nobel Prize for Treg research as elaborated in our Primer this month). We shall also see how thymic involution affects this balance over time, and how affinity maturation refines our immune response, all through the lens of selection from within.

V(D)J Recombination: the Blueprint of Diversity

Before the immune system can choose the right defenders, it first needs options: millions of them. Every B and T cell starts as a blank slate and then assembles its antigen receptor genes by randomly combining segments called V (variable), D (diversity), and J (joining).

This process, V(D)J recombination, is driven by the enzymes RAG1 and RAG2 (Recombination Activating Genes). They cut and rejoin DNA at specific sequences known as recombination signal sequences (RSS). The process is deliberately messy: extra nucleotides may be added or removed by another enzyme, terminal deoxynucleotidyl transferase (TdT). The result? An enormous variety of unique receptors.

Mechanistically, it’s like shuffling and slicing the genome’s deck to deal out millions of unique hands. Some combinations will recognize viral proteins, others bacterial toxins. And some, unfortunately, will bind self-antigens. At this stage, the immune system doesn’t know which are which. That’s where selection begins.

Somatic Hypermutation: Refining the Arsenal

Once a B cell encounters its first antigen, it doesn’t stop evolving. In specialized structures called germinal centers, these cells deliberately mutate the DNA of their antibody genes through somatic hypermutation (SHM).

The enzyme activation-induced cytidine deaminase (AID) converts cytosine to uracil in DNA, triggering error-prone repair processes that introduce point mutations, particularly in the regions of antibodies that bind antigen. This can raise or lower binding strength.

It’s risky, as most mutations hurt function, but this allows for rapid improvement of binding affinity. B cells with receptors that are even slightly more specific for their antigens are selected by helper T cells and antigen-presenting cells to proliferate. Others die off. This is survival of the fittest, molecular edition.

Together, V(D)J recombination and somatic hypermutation create and refine the raw variation upon which all the immune system’s later selection acts.

Central Tolerance: The First Line of Self-Policing

With so much random diversity, many new receptors inevitably recognize the body’s own molecules. The immune system prevents this through central tolerance, which happens early in cell development: in the thymus for T cells and bone marrow for B cells.

In the thymus, immature T cells are tested through two key stages:

1. Positive selection keeps cells that can recognize the body’s major histocompatibility complex (MHC) molecules, the platform most cells use to present both intracellular and extracellular peptides. If a T cell cannot interact with self-MHC at all, it dies.

2. Negative selection deletes those that react too strongly to self-antigens. Specialized thymic epithelial cells, using a gene called AIRE, express a wide range of tissue-specific proteins, ensuring T cells are tested against a realistic sample of “self.”

The surviving T cells, composed of cells that are potent enough to recognise MHC molecules but not potent enough to attack the body’s own cells, form the healthy repertoire that will later patrol the body. It’s a delicate filtering process that mirrors natural selection, only that it happens on a miniature scale, inside every person’s thymus.

Thymic Involution: When the Filter Wears Thin

Unfortunately, this selection system weakens with age. Starting as early as the first year of life, the thymus gradually shrinks and is replaced by fatty tissue in a process known as thymic involution.

As the thymus degenerates, fewer new T cells are produced, and the efficiency of negative selection declines. Older adults therefore rely heavily on their existing T-cell memory and produce fewer new Tregs (regulatory T cells). This contributes to the increased incidence of autoimmune diseases and reduced vaccine responses with age.

In other words, as our biological academy for training immune cells closes its doors, the risk of miseducated recruits sneaking into circulation rises.

Peripheral Tolerance: The Backup Brakes

As fascinating as it is, central tolerance is not perfect. It may allow a few self-reactive cells to escape into the bloodstream, wreaking havoc on our body systems. This risk increases as we age, hence our bodies need a safety mechanism to keep them in check. This is peripheral tolerance.

The stars of this system are regulatory T cells (Tregs), marked by the transcription factor FOXP3. These cells suppress excessive immune activation, secrete inhibitory cytokines like IL-10 and TGF-β, and can even directly suppress autoreactive T cells.

In 2025, the Nobel Prize in Physiology or Medicine was awarded to Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi for uncovering FOXP3 and the essential role of Tregs in immune tolerance (as elaborated in our Primer article this month). Their discovery explained why mutations in FOXP3 cause catastrophic autoimmune syndromes: without Tregs, the immune system loses its brakes.

Peripheral tolerance acts as a second checkpoint, ensuring that even escaped self-reactive cells remain harmless.

Affinity Maturation: Evolution in Real Time

When B cells meet their antigen again, during a secondary infection or booster vaccination, their antibodies aren’t just more numerous, they form a more precise fit for their antigen.

This improvement, called affinity maturation, results from rounds of mutation and selection within germinal centers. B cells that bind the antigen most tightly capture more of it, receive stronger help from T follicular helper (Tfh) cells, and undergo a greater degree of proliferation. Consequently, weaker binders die off.

The process cycles until the surviving clones produce antibodies of remarkably high affinity. It’s the immune equivalent of a species fine-tuning itself to its environment, except the timescale is weeks, not millennia.

Conclusion: The Evolutionary Logic of Immunity

Across all these mechanisms, from V(D)J recombination and somatic hypermutation to central and peripheral tolerance, one can note a clear pattern of variation and selection. The immune system constantly generates diversity, then shapes it through successive filters to balance recognition and restraint.

This interplay allows immune cells to 'evolve' in real time, protecting us from pathogens without attacking self. When any part of this process falters, be it through thymic involution, Treg dysfunction, or faulty selection, autoimmunity can emerge.

Understanding these parallels between cellular evolution and organismal evolution not only deepens our appreciation of immunology but also highlights how nature’s most powerful idea, selection, operates even within us.

References

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Image Credit: https://news.ucsb.edu/2024/021575/appetizer-can-stimulate-immune-cells-appetite-boon-cancer-treatments