Episode 2

To listen to this episode, click on one of the following links.

Recommended for Background Information

• Immune by Philipp Dettmer (ISBN 9780593241318)

• 2025 Nobel Prize in Physiology or Medicine, https://www.nobelprize.org/prizes/medicine/2025/press-release

Texts Discussed in This Episode

• “Protein Synthesis and Metabolism in T Cells” in the Annual Review of Immunology, by Linda V. Sinclair and Doreen A. Cantrell, in Annual Review of Immunology, https://doi.org/10.1146/annurev-immunol-082323-035253

• “Enkephalin-producing regulatory T cells in the skin restrain local inflammation through control of nociception” by Alejandra Mendoza et al., in Science Immunology, https://doi.org/10.1126/sciimmunol.adz6869

Transcript

Hello, and welcome to “If Socrates Had a Podcast”! I am your host, Vinay Kalva. In today’s episode, we will be discussing two scientific papers I had the pleasure of reading recently. The first, “Protein Synthesis and Metabolism in T Cells”, is a review article by Linda Sinclair and Doreen Cantrell published in the Annual Review of Immunology. The second, “Enkephalin-producing regulatory T cells in the skin restrain local inflammation through control of nociception”, is in the journal Science Immunology and reports on a study conducted by Alejandra Mendoza and their colleagues. If you are interested in reading these papers to learn more, you can find them linked in the podcast description. Both papers are, as of the publication of this episode, accessible to anyone free of charge.

Before we proceed with the dialogue, I will recommend two resources if you want to get some additional background, or to learn more. First, if you would like more detail regarding the basics of how the immune system works, I highly recommend that you consult the book Immune by Philipp Dettmer, the founder of the YouTube channel “Kurzesagt in a Nutshell”. You can find the ISBN of Immune in the podcast description; I encourage you to legally obtain a copy, whether through purchasing the book or by checking your local library. Second, while I was writing this episode, it was announced that the 2025 Nobel Prize in Physiology or Medicine was awarded to three discoverers of peripheral immune tolerance: Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi. Regulatory T cells, the focus of this dialogue, are a key part of this discovery, because they prevent the body from attacking itself. Accordingly, I highly recommend that you read the press release and additional resources available on the Nobel Prize website. You can find the relevant links in the episode description.

In today’s dialogue, Socrates will discuss the two papers with Marie Pasteur. Socrates, of course, is the namesake of this podcast. Marie Pasteur’s husband is the very famous Louis Pasteur; their last name is immortalized in the word “pasteurization” and associated with the foundational discovery of germ theory. I will play the parts of both characters, inflecting my voice as follows when I am Socrates: (inflect “I am Socrates”) and as follows when I am Marie Pasteur: (inflect “I am Marie Pasteur”). With that, let us begin our exploration of the fascinating world that is immunology.

SOCRATES: Thank you so much for letting me visit your and Louis’s laboratory, Madame Pasteur. It was quite informative for me to see where it all began.

PASTEUR: It is our pleasure, Socrates. Our laboratory would love to have new and excited scientists helping us advance our collective knowledge.

SOCRATES: I am sure you would. However, I am but a simple man, and given my propensity to think rather than do, I must say I am better off discussing and considering science, rather than doing it.

PASTEUR: Don’t underestimate yourself, Socrates! You are smart enough to join the laboratory. I can give you the application today if you would like.

SOCRATES: I must consider it, Madame Pasteur. However, I am feeling quite weary from the long journey to Paris. May we visit a café, get some coffee, and perhaps discuss some papers I was reading?

PASTEUR: Certainly we can, Socrates. Perhaps I can call Louis too, for he might want a word with you.

SOCRATES: It is perfectly fine, Madame Pasteur. He will come when he does, I suppose.

PASTEUR: In that case, let us go and enjoy some coffee, and discuss as we go.

SOCRATES: So the plan shall be. Now, I was reading two papers recently, and I found them most interesting.

PASTEUR: Were they ours?

SOCRATES: They were not yours. They were more recent ones, actually. I remember finding one of them in the dustiest stack of journals at the Academy. It was an article entitled “Protein Synthesis and Metabolism in T Cells”, by two presumably prestigious scientists named Linda Sinclair and Doreen Cantrell.

PASTEUR: I wonder why the stack was dusty. And the other?

SOCRATES: I can’t quite remember, but I think it was called “Enkephalin-producing regulatory T cells in the skin restrain local inflammation through control of nociception”. A very specific title, I must say. Where I found that article I don’t remember – it must have been from a visit a while back.

PASTEUR: I am most intrigued, Socrates. (pause) Well, it appears Louis has found us, for we have arrived at his favorite cafe.

SOCRATES: Well, the more, the merrier, I suppose.

PASTEUR: He seems quite busy, however, for he is reading something. Let’s not disturb him, and quietly continue talking about those papers you read.

SOCRATES: I must agree. Now, I must say that the two papers do not at all seem to be related.

PASTEUR: Why would you say that? Even papers that don’t seem related often are, and in unexpected ways, no less.

SOCRATES: As I said, I am a simple man, and I know very little. That, perhaps, is why I don’t think they are. I reason you could help me find the connection – if there is any, of course.

PASTEUR: Would you summarize the papers for me, so that I could perhaps be of more assistance to you?

SOCRATES: I certainly can. Let us start with “Protein Synthesis and Metabolism in T Cells.” This, being a review article, discusses the state of the field. From what I can gather, here were the essential points:

• First, T cells are always producing proteins whether or not they face a threat. However, the rate at which they produce proteins increases rapidly after an infection.

• Further, T cells produce their own proteins, which requires a large supply of energy. Accordingly, they have extensive mitochondria (the organelle which extracts energy from glucose) and a large number of glucose transporters. 

  • However, T cells commonly use glycolysis to produce energy despite its lower output. This is because the process involves producing molecules which are used in protein production.

  • Additionally, due to this high protein production volume, amino acid transporters are widely used, especially SLC7A5.

• Second, cytokines, including IL-15 and especially IL-2, play an essential role in ensuring continued growth of T cells.

• There are several actors, and points of failure, in increasing the rate of protein production.

  • If T cell receptors do not work, or if T cells do not interact with cytokines, they do not increase their rate of protein production.

  • Myc, a transcription factor, regulates protein production. When there are abundant threats, Myc levels are higher. Further, Myc relies on glucose and is thus affected by glucose transporter presence and functionality.

  • mTORC1 regulates the replication of CD4 and CD8 T cells specifically and plays a role in regulating protein production. How exactly the latter function works requires further quantitative study.

• Finally, here are a few major unanswered questions about T cells:

  • How do T cells maintain the minimum level of protein production that we know they do?

  • How do other types of T cells, including regulatory T cells, regulate protein synthesis?

  • What about T cells that can’t target disease, called exhausted T cells? They are common in chronic infections and tumors, and we don’t know why they exist or how protein production works for these specific T cells.

PASTEUR: This seems like a very interesting paper, Socrates. What about the other one?

SOCRATES: The other paper, “Enkephalin-producing regulatory T cells in the skin restrain local inflammation through control of nociception”, was some very new research in the field, and there was quite a lot of information in it. I found it quite difficult to parse.

PASTEUR: It makes sense that you would find it difficult. Let us work through it together.

SOCRATES: How should I start? I have read many papers of yours, but even with that experience it’s not particularly clear to me.

PASTEUR: Well, Socrates, start off with this: What are the questions that the paper aims to answer, as you understand it?
SOCRATES: Well, the Methods section said that the research aimed to answer the following questions:

1. Do regulatory T cells affect sensory neuron activation?

2. Do regulatory T cells, by modulating neurons, control skin inflammation?

3. Are only certain types of regulatory T cells capable of modulating neurons?

4. How exactly do regulatory T cells modulate target neurons? 

PASTEUR: I suppose that’s a place to start. What did the authors think were the answers to these questions?

SOCRATES: I can’t read their minds, but the paper seems to suggest that the answers were: Yes for the first two questions, and perhaps for the third. For the fourth question, the proposed explanation here is that action on peripheral neurons is responsible for modulating neurons.

PASTEUR: Now, Socrates, let us turn our attention to the experiments. 

SOCRATES: It seems we are doing the scientific method here, Madame Pasteur. Would you not agree?

PASTEUR: I would agree with you. It helps to think this way, because the purpose of everything becomes clearer. Now, tell me about the experiments that the authors conducted and described. 

SOCRATES: It seems to me that the first part of the Results section within the paper answers the first question: Do regulatory T cells affect sensory neuron activation? To answer this question, the authors applied diphtheria toxin to the ears of mice so that T cells became non-functional from a lack of protein production. Here is the argument I see they have developed, based upon their findings:

1. The authors found that sensory neurons are measurably close to T cells.

2. Applying diphtheria toxin to mice ears for a short period led to increased observed sensitivity to heat, cold, and movement in response to a stimulus. Female mice did not see a significantly increased response to heat, but the authors did not think that inflammation was responsible for this.

3. The two key confounding variables – increased production of cytokines and total immune cell content – were not affected by either diphtheria toxin or capsaicin.

4. Given the above, the authors conclude that regulatory T cells do affect sensory neuron activation, because preventing them from functioning leads to effects on heat and cold detection, as well as movement in response to a stimulus.

PASTEUR: I suppose the key premise here is that regulatory T cells play a role in whether or not sensory neurons activate. However, I wonder why those female mice did not respond to heat.

SOCRATES: I suppose it’s an interesting question. However, there are many more unanswered ones, I am sure, in the rest of the paper.

PASTEUR: Certainly there are. If we move on we can find out more.

SOCRATES: Let’s see, then. What was it? Hmmm… Yes! Now I remember what that experiment was about. It checked a very specific mouse model, and then in a second part the authors killed off the mice’s regulatory T cells with diphtheria toxin to determine if regulatory T cells affected inflammation through sensory neurons. I assessed the argument to be the following:

1. Sensory neurons have been established in a prior experiment to start inflammation, and immune cells play a role in this.

2. When the prior experiment’s findings were tested, the result was consistent with the original model.

3. Then, during the second part of the experiment, the authors examined the lymph nodes, and found that fewer T cells turned on and fewer cytokines were produced.

4. However, the neurons of interest were still turning on and there was more observed inflammation.

5. Thus, inflammation which occurs due to reduced regulatory T cell content depends on the sensory neurons.

6. The authors thus argue that regulatory T cells prevent the neurons from activating too much during early inflammation.

PASTEUR: How exactly does the sixth premise follow from the fifth? It is not particularly evident to me.

SOCRATES: I think the authors are merely taking the information they have and integrating it into the prior model I mentioned first, which they tested and found to be true. How much of a problem or an asset this is is a topic we can discuss afterwards if needed.

PASTEUR: I agree with you. Now, I suppose it will be useful if we take the author’s claim to be plausible merely for the purpose of analyzing the rest of the paper. We can question the claim further if the rest does not hold up to scrutiny.

SOCRATES: I suppose this works. Now, regarding the third question: Are only certain types of regulatory T cells capable of modulating neurons? It seems the answer is related to a specific gene called Penk. The third and fourth sections of the Results explain this: the third where Penk is present, and the fourth how it is expressed. Understanding this part was quite a challenge: I needed to find and read the supplementary information just to get an idea.

PASTEUR: You are not the only one, Socrates. Sometimes in my own practice, I have needed to read the supplementary information just to understand the basics of what occurs in the paper. However, it seems that information is most useful when I try to replicate the results.

SOCRATES: I don’t think we are at that point yet, Madame Pasteur. Regardless, this  makes sense to me now. Here is the argument that is being made, as I sense it.  

In the third section, the authors searched for genes that could explain the anti-inflammatory actions of regulatory T cells. One promising result was Penk, the gene that I told you about earlier. Based upon this, the argument seems to be:

1. Penk is highly expressed in the skin. 

2. Neurons and regulatory T cells are close together, so they likely communicate with each other. 

3. Regulatory T cell activation and having lots of T cell receptors were more prevalent in a cluster of cells with a history of Penk expression, which also had the highest rate of replication. 

Based upon this, the authors conclude that Penk regulates regulatory T cell responses to inflammation.

The fourth section discusses which receptors were involved in Penk expression. The argument they made was this:

1. Regulatory T cells without T cell receptors have less Penk expression than those with T cell receptors.

2. However, T cell receptors alone are insufficient to cause Penk expression, because lymph tissues do not express the gene if those receptors alone are stimulated.

3. Glucocorticoid receptors expressed Penk in tumor and neuroendocrine cells, so they seemed a plausible second target.

4. Regulatory T cells had their glucocorticoid receptors activated with dexamethasone, a substance which causes them to act; this did lead to Penk expression.

Based upon these findings, the authors concluded that the Penk gene is expressed when both T cell and glucocorticoid receptors are activated. 

Thus, it seems the answer to the question is that regulatory T cells with T cell and glucocorticoid receptors, and especially those regulatory T cells in the skin, regulate anti-inflammatory responses.

PASTEUR: That’s a relatively intricate argument, I must say. I am curious about that supplementary information, though. Did you find anything else in there?

SOCRATES: Yes. I was curious why they chose to only analyze Penk. Figure 4A in the supplementary information seems to show that another gene, Rln3, is also a viable candidate. 

PASTEUR: Perhaps you could think about it again, Socrates, or find it.

SOCRATES: I remember packing the supplementary material. While I look for it, Madame Pasteur, perhaps we can get some food. We have long exhausted our coffee.

PASTEUR: I agree, Socrates. Why don’t we visit a boulangerie, so you can try a freshly made baguette?

SOCRATES: Certainly. Let us do it, and I will figure out the answer in the meantime.

This regularly scheduled program is interrupted for a short break.

Dear listeners,

Socrates and Marie Pasteur are currently finding high-quality baguettes from a local boulangerie near the lab. You may be wondering how Socrates met Marie and Louis Pasteur, particularly the former. Well, I happened to meet all of them shortly before they engaged in this conversation. It was quite a fascinating story, so let me tell it to you.

The Pasteurs had recently published a paper and were quite bored of working in the lab all day and all night over the past year. They thus decided to take a holiday, and traveled from Paris to the United States to see the World’s Fair in Chicago. After a long and very dangerous ship across the Atlantic Ocean, and a similarly dangerous but (thankfully) much shorter train journey from New York, they were quite tired and looked first for snacks at the fair. They came across a machine making something called popcorn. Louis and Marie asked, paid for, and received two bags each. As they searched around the fairgrounds for an open place to eat, they noticed a most curious figure, dressed in a tunic, following them. Assuming it was one of those irritating people who kept following them, believing that they were mystics who could cure their illness, they ignored this person and attempted to find something scientific amidst all the crowds – and also, of course, to lose him. However, the tunic-clad figure caught up to them, and said,

“Excuse me, Monsieur and Madame. I would like to speak with you for a moment.”
“Who are you?!” exclaimed Louis.

“Socrates is my name, Monsieur,” replied Socrates. “I have heard of your work regarding the source of illness.”

“Our work, you mean!” said Marie.

“Absolutely, our work!” Louis concurred.

“I’m sorry, I didn’t know that it was both of you, Monsieur and Madame. All the papers of yours that I read had no names on them; I was making my determination based off of celebrity, and only Monsieur has been highlighted in the newspapers.”

“Well, we must be going. We have too many admirers to meet, especially in this place,” said Louis.

“As you wish, Monsieur…and Madame. I shall take your leave.”

Marie and Louis continued searching the fair for more food, noticing a few more curious fellows following them. The two were worried.

“Why are there so many people following us right now?” pondered Marie aloud.

“I suppose it’s because of our work. We did, after all, work on germ theory, and invented pasteurization; we also did so many experiments,” Louis considered.
“And that fellow we just met. Is he that famous philosopher from antiquity?”

“I think it is. Who else would it be?”
“The Greek gods, perhaps. After all, it is starting to rain. Is Zeus cursing us?”

“Zeus? In Chicago? Unlikely. But oh, the rain –”

Indeed, it was starting to rain. People all around were running to the nearest buildings they could find to shelter; a few calmly pulled their umbrellas out, as did Louis and Marie. As they pulled out their umbrellas and continued walking, they saw Socrates, lacking an umbrella and soaking wet. He had no idea where to go, either.

“That Socrates! He’s wet and cold!” said Louis, genuinely appalled.

“Why not help him?” said Marie. “Let’s lend him one of our spare umbrellas; we packed so many, after all, given the wind gusts and terrible rain of the ocean.”

Louis and Marie walked up to Socrates and gave him an umbrella.

“Thank you, Monsieur and Madame,” said Socrates. “I want to see your laboratory. Would you be able to invite me to Paris to check it out?”

“You said you read all of our papers, right?” said Louis.

“I did, Monsieur,” said Socrates. “Now I want to know how you got there.”

“Well, we cannot say no to those who are most inquisitive about our lives’ work,” said Marie. “Come with us, and we will book you a ticket.”

“I appreciate your invitation, Madame, and I accept it unequivocally,” said Socrates.

Socrates, ticket in hand, came back to Paris with Louis and Marie, after the fair. He and Marie spoke on several occasions during the long journeys on the trains and ships, culminating in the discussion that you have the pleasure of hearing now. I suppose they had tape recorders, which is how this conversation ended up on this platform. Regardless, I have taken up plenty of your time, so I will let you continue your journey of scientific enlightenment.

At this time, we return to our regularly scheduled program.

PASTEUR: I hope you enjoyed the baguette. I certainly enjoyed mine.

SOCRATES: Indeed I did. The crisp crust contrasts very nicely with the soft interior.

PASTEUR: Now, did you figure out that graph you mentioned earlier?

SOCRATES: Of course. I took a look, and it seems I did misinterpret the graph. It seems Rln3 causes lots of protein to be made whether the regulatory T cells are active or not. No wonder the authors did not examine it.

PASTEUR: The question I had is why they bothered to re-examine regulatory T cell proximity to axons when they already established that. I think they used different mice, which is why they did it.

SOCRATES: This explanation makes sense. Now, I want to answer the fourth question: How exactly do regulatory T cells modulate target neurons? With all the information we have, the mechanism should be clearer.

PASTEUR: Let’s see what we get with that.

SOCRATES: Certainly. From what I recall, the fifth and sixth sections of the Results answer this question.

Starting with the fifth section, there are two relevant experiments. In the first, the researchers killed Penk-expressing regulatory T cells by making mice which expressed the diphtheria toxin receptor. As a result, cells in the skin but not the lymph nodes were killed. Simultaneously, heat responses, inflammation, and neuron activity all increased, while the key confounding variables – production and activation of effector T cells and cytokines – did not change. In a second experiment, only those regulatory T cells which did not express Penk were killed. However, this time heat sensitivity, neuron activation, and lymph node inflammation did not change significantly. Additionally, mice which did not have Penk had less skin inflammation than those which did, but there was no significant difference in skin inflammation between mice with Penk and control. The authors posited that the lost Penk-expressing regulatory T cells were replaced by regulatory T cells which did not express Penk, and that these regulatory T cells would no longer reproduce. Thus, taking these findings together, the researchers argued that Penk-expressing regulatory T cells regulate the activation of neurons responding to stimuli.

PASTEUR: I wonder how the authors could argue that the loss of Penk-expressing regulatory T cells was mitigated by regulatory T cells which did not express Penk. Also, what exactly causes the action?

SOCRATES: I was confused as well. However, to answer your question: Earlier in the paper, we learned that Penk codes for proenkephalins, which are the precursors of enkephalins. This, it seems, is the answer.

PASTEUR: Why do the authors think this is true?

SOCRATES: The answer seems quite complex. First, the prior knowledge: it is known that enkephalins act on opioid receptors, leading to three consequences. These are: protein-releasing neurons release fewer proteins; neurons more broadly are rendered inactive; and skin inflammation is reduced. To determine the role that enkephalins have in the activation of neurons responding to stimuli, the authors deleted Penk in regulatory T cells of mice. Over 4 weeks, more neurons were activated in the dorsal root ganglia, but inflammation and immune activation were largely unchanged relative to control mice. The mice not expressing Penk showed more sensitivity to heat (in males) and mechanical stimuli (in both males and females), but cold sensitivity was not significant. Thus, the authors inferred that neuron activation increased slightly and concluded that cold sensitivity was regulated by regulatory T cells, but not by the Penk gene specifically. Incorporating the prior knowledge, this means that enkephalins do not regulate cold responses by regulatory T cells. 

To further test the role of enkephalins, the authors used the mouse model we discussed earlier. Removing the Penk gene in these models led to more neuron activation and inflammation in the early stages of infection. Further, opioid receptors were expressed only in neurons; knowing that Penk expression makes enkephalins, and enkephalins stimulate opioid receptors, the conclusion is that Penk-expressing regulatory T cells act only on neurons. We also know from before that these cells regulate sensory neurons and the inflammation these neurons cause. In a further experiment, the researchers established that removing these T cells' specific function in stimulus response was not required to affect skin inflammation. Thus, we can establish the following causal pathway: Penk → Penk mRNA → proenkephalin → enkephalin → opioid receptor → reduced neuron activation → reduced inflammation.

Lastly, through a thorough analysis of the dorsal root ganglia, a region with many types of neurons, the authors found that different types of neurons have different response levels to opioid receptors. Given the previously established pathway, we can see how regulatory T cells regulate inflammation by expressing Penk, and that they affect different types of neurons.

PASTEUR: I assume the answer to the last question, then, is that pathway which you  established. Now, Socrates, would you like to discuss how the papers relate?

SOCRATES: Certainly. I suppose it will be beneficial to start with the relevant unanswered questions from the review. First, I am curious how exactly T cells maintain the minimum required level of protein production. 

PASTEUR: Well, if we are speaking strictly about regulatory T cells, I think the function of regulatory T cells justifies maintaining the minimum level of protein production. After all, tackling inflammation, especially in the skin, is very much a necessity. 

SOCRATES: Your point is true, Madame Pasteur, but it does not specifically address how exactly regulatory T cells maintain that minimum level of protein production.

PASTEUR: I must disagree slightly here, Socrates. The why is as important as the how; without the why, there cannot be a how. In any case, given that inflammation is a common and always possible occurrence, it seems plausible that regulatory T cells would need to be ready to tackle it at all times. Additionally, if we take a look at the anti-inflammatory pathway that you developed, there are multiple ways that a regulatory T cell could constantly synthesize proteins.

SOCRATES: The review, however, said that T cell protein production only increases “after an infection”. Can inflammation be an infection? Also, if protein production only increases after an infection, what would be produced when there is no infection?

PASTEUR: Inflammation is not an infection, but rather a possible response to infection. Thus, in our case, the presence of inflammation would indicate that there is an infection. Additionally, here are a few possible stoppage points: First, if there is no infection and no need for inflammation, the pathway could stop after proenkephalin synthesis, and prevent conversion to enkephalins. Second, the pathway that you devised earlier does not include the T cell receptors and glucocorticoid receptors that we earlier established regulate Penk expression. The review also states that T cell receptors are essential to increasing protein production. Taking these together, we can add these to your pathway, and see that if T cell receptors are not stimulated, then Penk will not be expressed.

SOCRATES: I am not particularly confident in the first proposal, given that there is no clear reason given by either the paper or the review to suggest that protein synthesis would be blocked. Regarding your second proposal, in your modified pathway, are we assuming that the mechanism of action by which enkephalin protein production specifically is increased is T cell receptor action?

PASTEUR: There is no other conclusion that makes sense. The only confounding variable here is glucocorticoid receptor action.

SOCRATES: In the experiment we discussed, glucocorticoid receptors are tested because the Penk gene has binding sites for them, and such receptors' activation in other cells happens to work out. However, if I remember correctly, there were several other factors mentioned that could possibly be confounding variables.

PASTEUR: Do you remember what these factors were?

SOCRATES: I do. However, from what I recall, the paper does not address these as possibilities because they either help with transcription or signaling, or they occur after expression.

PASTEUR: That would lend support to my theory that the only relevant confounding variable is the glucocorticoid receptors. Additionally, there is no valid reason to assume that they are not involved in protein synthesis, given that they cause Penk expression and thus the production of enkephalins.

SOCRATES: I am inclined to agree. On this basis, what would you conclude?

PASTEUR: On this basis, we have an explanation for how regulatory T cells maintain the minimum level of protein production. Continuous activation of T cell receptors and glucocorticoid receptors ensures that regulatory T cells constantly produce proteins, even minimally.

SOCRATES: Is this explanation not only applicable to the Penk gene? I find it hard to agree with the latter generalization, especially given that the glucocorticoid receptors are specifically found near the gene.

PASTEUR: I would argue that I am merely inducing. In the new study, activation of T cell receptors is not sufficient, and adding that of glucocorticoid receptors ensures that regulatory T cells constantly produce enkephalins. I am merely arguing that this same mechanism, or perhaps a similar one, likely also leads to other proteins being expressed.

SOCRATES: I suppose that is an interesting research question to explore. At least we know that T cell receptors start the signaling cascade which leads to gene expression in regulatory T cells.

PASTEUR: Is that not the second unanswered question?
SOCRATES: I suppose it is. The answer to that question – how T cells, including regulatory T cells, regulate protein synthesis – seems to be that T cell and glucocorticoid receptors do it. Thus, regulatory T cells, at least, regulate internal protein synthesis the same way that other T cells do, as described in the review. It did have one more question, however.

PASTEUR: What was it?

SOCRATES: Well, it was what pathways regulated the amino acid transporters, ribosomes, and general activity that we discussed earlier.

PASTEUR: Unfortunately, it seems the paper you discussed does not explain how amino acid transporters or ribosomes were regulated. The general activity question is partially answered by this paper, however.

SOCRATES: How is it answered, Madame Pasteur?

PASTEUR: Well, Socrates, we found that specific pathway from reception to reduced inflammation. The review’s statements about the signaling pathway from the T cell receptor to the gene are not contradicted by this new study from what we have discussed, so that goes in your pathway as well.

SOCRATES: Indeed, we did.

PASTEUR: We also know that regulatory T cells do regulate inflammation and responses to stimuli; after all, the paper found that out.

SOCRATES: This is true, indeed.

PASTEUR: Additionally, these activities are very much part of the general activity of regulatory T cells.

SOCRATES: I cannot object.

PASTEUR: There is your answer, then. This new paper does help answer the review’s unanswered questions – if we are to take its logic to be accurate and true.

SOCRATES: Now that is an entirely separate discussion, although there is one question that yet remains unanswered for me.

PASTEUR: What question is it?

SOCRATES: How does the response to stimuli affect inflammation, exactly? The title says it does, but it is not clear from the paper how this occurs.

PASTEUR: Well, we should keep building on the pathway you proposed. We are at receptor activation, so there must be a connection that ends at the receptor.

SOCRATES: That seems plausible, although I have a mechanism of my own in mind. What did you think?

PASTEUR: I would argue that there must be some sort of stimulus to the glucocorticoid or T cell receptors which starts the signaling cascade.

SOCRATES: What stimuli were you thinking of?

PASTEUR: I was thinking that perhaps the neurons stimulate the receptors in some way.

SOCRATES: Consider this: T cell receptors would be acted upon by antigens, and glucocorticoid receptors by glucocorticoids.

PASTEUR: Of course – neurons cannot release antigens. Could neurons not release glucocorticoids, however?

SOCRATES: This seems unlikely. How would tumor cells, a basis of the justification the paper authors made, respond to neurons? Tumors, being outgrowths, by definition would not respond directly to neural signaling.

PASTEUR: You are probably correct. Instead, I think a more plausible argument is that neuron-neuron communication would eventually lead to the neurons stimulating inflammation, but that regulatory T cells inhibit this process as we have discussed.

SOCRATES: I am more inclined to accept this explanation. Unfortunately for us, however, it is sunset. I must be going back home soon.

PASTEUR: That is most unfortunate. Would you like to join Louis and I for dinner before you leave?

SOCRATES: I most certainly will. He might be interested to hear about what we have discussed.

PASTEUR: I am most sure. Let us go quickly.

This concludes the second episode of “If Socrates Had a Podcast”. As noted in the beginning, you can find the papers and other resources in the podcast description. If you have any questions or would like to suggest books or notable people that I should feature on this podcast, reach out by sending me an email at ishap.podcast@gmail.com. That’s i-s-h-a-p.podcast@gmail.com.

I hope that you learned something new and exciting today, and enjoyed the brief intermission. If you like what you heard, stay tuned for my next episode, coming up in two weeks. Thank you very much for your time, and have a wonderful day.