Trained Immunity, Part 4

ISSUE N.4

The Science & Significance of Trained Immunity

A foundational 2002 paper by Gordon Brown and colleagues helped answer that question by establishing Dectin-1 as the major β-glucan receptor on macrophages.

Dectin-1 is a pattern recognition receptor expressed predominantly on innate immune cells, including macrophages, monocytes, dendritic cells, and neutrophils. The receptor recognizes β-glucan structures characteristic of fungal cell walls, allowing immune cells to detect a conserved molecular feature of fungi rather than needing to identify each fungal species individually.

Brown and colleagues demonstrated that Dectin-1 plays a major role in how macrophages recognize β-glucan. When the researchers blocked Dectin-1, macrophages largely lost their ability to recognize the β-glucan in yeast particles.

Notably, the experiments showed that neither CR3 (complement receptor 3) nor the mannose receptor accounted for this particular nonopsonic recognition pathway, helping resolve a decades-long controversy over the identity of the macrophage β-glucan receptor. We will go into CR3 in a future newsletter.

Later work has filled in more of the story. We now know that Dectin-1 is selective about the β-glucan structures it recognizes. The receptor is highly specific for a pure β-1,3-linked backbone, and even within that family it does not treat all β-glucans equally – measured binding affinities span roughly nine orders of magnitude depending on backbone chain length and β-1,6 side-chain branching.

Presentation turns out to matter as much as structure. Particulate β-glucan clusters Dectin-1 at the cell surface into what has been described as a phagocytic synapse, excluding inhibitory phosphatases and allowing signaling to proceed. Small soluble β-glucans can occupy the receptor without triggering that response. The same molecular pattern, presented differently, does not deliver the same signal.

So the answer to the question we started with is actually practical: recognizing β-glucan gives the innate immune system a way to detect a conserved component of fungal cell walls and initiate an appropriate antifungal response.

β-glucan recognition is part of host defense, playing an important role in protection against fungal infection.

The biological importance of that recognition becomes even clearer when we look at fungi themselves. Several pathogenic fungi can conceal β-glucan from Dectin-1 – through cell-wall masking or changes in β-glucan exposure – providing another line of evidence that this host-recognition pathway matters in antifungal defense. We evolved a way to see it, and fungi evolved ways to hide it.

And here's where this becomes even more interesting in the context of trained immunity. β-glucan recognition doesn't only participate in the immediate response to fungi. Under experimental conditions, β-glucan exposure can functionally reprogram innate immune cells so that they respond more strongly to later challenges – including signals unrelated to the original fungal encounter. In other words, the significance of this ancient fungal-recognition system extends beyond antifungal defense into the broader immune readiness we're beginning to understand through trained immunity.

That answer somehow makes the question even more interesting to me.

The body didn't wait for us to understand fungal immunology before it knew what to do with a fungal encounter. It already had a recognition system in place – one capable of identifying a meaningful molecular pattern and using that information to help determine what should happen next.

This is where I come back to something AJ Lanigan (my mentor on trained immunity and the formulator of BWH-85® — more on him later!) said recently on a webinar that I played back to write down: “The number of immune cells that a person has is self-regulated by a competent immune system.”

AJ described this to me as noetic wisdom—a kind of knowing that exists beyond what we can arrive at intellectually. That language resonates deeply with me because it gets at something I've trusted throughout my career: the healing power of nature and the body's inherent capacity to regulate and heal itself.

The immune system isn't waiting for us to tell it how many macrophages to make, when tissue needs to be repaired, or which molecular patterns deserve its attention. A competent immune system is continually receiving information, interpreting context, coordinating resources, and adjusting its response.

And that brings us right back to trained immunity.

Before an innate immune cell can adapt to an experience, something has to be recognized. Before the metabolic and epigenetic reprogramming we've been talking about can occur, a biological signal has to enter the conversation.

β-glucan is one of those signals.

Dectin-1 is one of the ways the immune system recognizes it.

And rather than making me want to micromanage that process, understanding it makes me trust the intelligence of the system even more. My question as a clinician becomes less about how I can force an immune response and more about whether I can provide biological signals that support the immune system's own capacity to recognize, coordinate, adapt, and respond appropriately.

That's the connection I don't want us to lose as we go deeper into the mechanisms of trained immunity. The goal isn't more immune activity. It's greater immune capacity and coordination.

Next Issue:
So what actually happens when β-glucan binds Dectin-1?

Recognition is only the beginning. Once Dectin-1 recognizes β-glucan, signaling begins inside the cell – and this is where we start to see how recognition can become functional change. How does a signal at the cell surface ultimately change the way an innate immune cell behaves?

References
Brown GD, Taylor PR, Reid DM, Willment JA, Williams DL, Martinez-Pomares L, Wong SY, Gordon S. Dectin-1 Is a Major β-Glucan Receptor on Macrophages. Journal of Experimental Medicine. 2002;196(3):407–412. doi:10.1084/jem.20020470. PMID: 12163569. PMCID: PMC2193936.

Quintin J, Saeed S, Martens JHA, et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe. 2012;12(2):223–232. doi:10.1016/j.chom.2012.06.006. PMID: 22901542. PMCID: PMC3864037.

Goodridge HS, Wolf AJ, Underhill DM. β-glucan recognition by the innate immune system. Immunol Rev. 2009;230(1):38–50. doi:10.1111/j.1600-065X.2009.00793.x. PMID: 19594628. PMCID: PMC6618291.

Goodridge HS, Reyes CN, Becker CA, et al. Activation of the innate immune receptor Dectin-1 upon formation of a 'phagocytic synapse'. Nature. 2011;472(7344):471–475. doi:10.1038/nature10071. PMID: 21525931. PMCID: PMC3084546.

Adams EL, Rice PJ, Graves B, et al. Differential high-affinity interaction of dectin-1 with natural or synthetic glucans is dependent upon primary structure and is influenced by polymer chain length and side-chain branching. J Pharmacol Exp Ther. 2008;325(1):115–123. doi:10.1124/jpet.107.133124. PMID: 18171906.

Rappleye CA, Eissenberg LG, Goldman WE. Histoplasma capsulatum α-(1,3)-glucan blocks innate immune recognition by the β-glucan receptor. Proc Natl Acad Sci U S A. 2007;104(4):1366–1370. doi:10.1073/pnas.0609848104. PMID: 17227865. PMCID: PMC1783108.

Ballou ER, Avelar GM, Childers DS, et al. Lactate signalling regulates fungal β-glucan masking and immune evasion. Nat Microbiol. 2016;2:16238. doi:10.1038/nmicrobiol.2016.238. PMID: 27941860. PMCID: PMC5704895.