From cellular stagnation to immune-cell fate: a thermodynamic perspective

What happens to a cell when it stops moving? Not when it stops migrating, but when its dynamic state is reduced—when interactions, exchanges and activity become constrained? Could cellular motion itself be part of the conditions that sustain life?

This question did not begin with an experiment. It began much earlier, during my postgraduate training, when I studied the cell in depth, particularly mitochondrial function and the energetic principles underlying cellular life. Thermodynamics provided a way of looking at biology. A living cell is not a static structure. It is an organized system maintained far from equilibrium through exchanges of matter and energy with its environment.

This perspective left me with an intuition: life depends on dynamics. Biological organization should not be confused with physical stillness. Maintaining the organized state of a living cell requires molecular activity, energy transformation and exchange. When these processes decline, the system may no longer be able to maintain its living state.

This also shaped my view of immunology. An immunologist cannot fully understand immune-cell behaviour without first understanding the cell. Immunology draws on cell biology, biochemistry, physics, chemistry and mathematics—not because an immunologist must become a specialist in all these disciplines, but because some biological questions require concepts that extend beyond a single field. Specialization and interdisciplinarity are not opposites. For me, this has meant continuing to explore, independently, concepts outside my field whenever they could help me understand a biological question.

Years later, this intuition returned to me through an experimental observation.

We were studying peripheral interleukin-2-stimulated natural killer (NK) cells from healthy individuals and patients with solid cancers. Our experimental system contained a physical variable: the cultures were either shaken or maintained without shaking.

At first glance, this might appear to be a technical difference. But the biological consequences were not trivial. In the absence of shaking, survival of NK cells from patients with solid cancers was reduced. Shaking altered survival, proliferation and cytokine responses, while also affecting apoptosis-related responses. The presence of red blood cells (RBCs) introduced another layer of complexity: RBCs modified NK-cell responses, and their effects depended on the dynamic conditions of the culture. Under a particular combination of high-dose interleukin-2, RBCs and absence of shaking, NK cells also acquired a Foxp3-associated regulatory phenotype.

Our 2020 study therefore raised an unusual possibility: cellular stagnation may itself be biologically relevant.

There was also a reason why RBCs had attracted my attention.

As a child, I used to watch the postman circulate through our neighbourhood, moving from house to house and delivering letters. He seemed to know every street and every household. Years later, I found myself thinking of the circulating red blood cell in a similar way—not as a messenger in the literal sense, but as a mobile cellular element continuously travelling through the body and passing through changing cellular environments.

That analogy prompted a question: could the presence and movement of RBCs influence neighbouring cells in ways that extend beyond their classical role in oxygen transport?

This question became intriguing in the context of immune cells.

Importantly, the concept I am considering is not simply cell migration. Migration describes the directed movement of a cell through space. Cellular motion is broader. A cell can remain in one anatomical location while being dynamic: changing its shape, remodeling its membrane, interacting with neighbouring cells, exchanging metabolites and signals, trafficking intracellular components and continuously transforming energy.

Conversely, what happens when this dynamic state becomes constrained?

This is where I believe thermodynamics may provide a useful conceptual framework.

Living cells are nonequilibrium systems. They maintain organization through energy transformations and exchanges with their surroundings. Entropy, enthalpy and Gibbs free energy describe different aspects of these energetic relationships. They should not be reduced to the simplistic statement that “disorder is life and order is death.” Yet thermodynamics allows us to ask a deeper question: could changes in cellular dynamics be associated with changes in the energetic state that supports cellular function and survival?

Perhaps cellular stagnation is not merely the absence of movement. Perhaps it represents a change in the physical and energetic conditions of the cell.

This possibility opens a perspective for immunology.

We already know that immune-cell fate is influenced by receptors, cytokines, transcriptional programs, metabolism and interactions with the microenvironment. Immunometabolism has established that the metabolic state of an immune cell can profoundly influence its function and fate. But could there be another dimension—one concerned with the dynamic physical state of the cell?

Could cellular motion influence energy exchange? Could changes in motion alter the cellular free-energy landscape? Could prolonged stagnation contribute to a transition from an active functional state toward dysfunction, regulation or death?

The observation involving RBCs adds another dimension. If circulating RBCs continuously move through different cellular environments and can modulate immune-cell responses, then the physical context of immune regulation may deserve more attention. Molecular signals and metabolic pathways may not be the only variables shaping immune-cell fate; the physical dynamics of the cellular environment could also matter.

I do not regard this as a completed theory. It is a scientific question that has gradually emerged from the intersection of cell biology, immunology, experimental observation and thermodynamics.

The next step, therefore, is not simply to ask whether an immune cell migrates, what molecules it expresses or which metabolic pathway it uses. We might also ask:

What is the dynamic state of the immune cell?

How much physical activity does it maintain? How does it exchange energy and matter with its environment? What changes when that activity is progressively reduced? Can immune cellular dynamics be quantitatively measured and related to metabolism, energy dissipation, free-energy changes and ultimately immune cell fate?

A simple experimental manipulation—shaking or not shaking a cell culture—unexpectedly opened a much larger question.

Could movement itself be one of the physical conditions of immune-cell life?