CD8

So it will be really important to further investigate those cell types.

Also, the CD8-Temra findings are pretty striking.

Right.

And you talk about whether that's cytokine-driven or TCR engagement.

Yes, absolutely.

Again, I am glad you brought this point.

So we found this, there's a memory popular, there's a CD8 memory, there are different types.

There's an effector memory, there's a central memory, and there are these Tamra populations.

Now, these are going to be phenotypic markers on T-cells.

CD8 positive, CD45RA positive, CD57 positive cells.

And that's about what they had an elevation of is about an elevation associated with a percent increase of about 42% compared to the controls where the elevation was only about 24%.

So they doubled that phenotype.

Now these are CD8 positive cells, which are component of cytotoxic T lymphocytes.

Okay? So the TCS exhibited a trend toward an increment in CD28 minus cells.

And that's a group of pro-inflammatory cells that increase gradually with age.

It's a very complex Gordian knot and you have to Put yourself in the literature.

What we observed was that in the spleen of older mice, these cells on the CD4 compartment were high.

and also on the CD8 compartment were high, which led us to ask that it could be because of a functionality defect in the T follicular helper cells that led to the delayed mycobacterial clearance.

which led us to do a proteomics experiment on the splenic CD4 T cells, which led us to capture MTB infection-induced alterations as well as treatment-induced alterations in old mice.

We found two enzymes, 4-hydroxy-2-oxyglutarate aldolase and aspartate aminotransferase to be deregulated in older mice.

And we are able first to characterize the sample, as we showed in the paper, that these models are mimicking the sample of origin.

in terms of subtypes constitutions, so B, T, CD4, CD8, but also minor subtypes such as NK or even gamma delta T cells.

We also showed that the immune checkpoint profile also mimics the sample of origin.

we showed that they are reconstituting the immune microenvironment of the pathology.

It's small possibility that it's TPO antibodies.

The bigger driver of damage to the thyroid gland tissue is CD8 cells and the particles they release that damage the cells.

TH1 cells, TH17 cells, and the cytokines they release.

Those are the things that drive most of the damage to the tissue.

As far as I'm aware, they're not going through the bloodstream, penetrate penetrating through the cell wall, getting inside the follicle and actually penetrating.

binding to things there and actually creating the damage.

More likely what's happening is there's inflammatory damage by the CD8 cells, the Th1 cells, the Th17 cells, the thyroid cells themselves, and we could talk about that mechanism if you want, And then when you have the destruction and now TPO and thyroglobulin start entering the bloodstream, now the antibodies are binding to those things more like a cleanup crew than they're actually creating the damage.

So when you look at lymphocyte map panels, you can see in somebody who's got a thyroid condition, there may be TH1, TH17, CD8 dominant, one or a combination of those.

But you also have inducible T regs.

Now, what do they do? You'll recall they're all coming from a CD4 positive T cell population, not the s- not the CD8.

Well, they're gonna regulate.

That is, they're gonna suppress, these are suppressor cells for the entire lymphoid response.

So we didn't leave that kind of technology.

So that means, remember, the pharmaceutical companies, along with the biomedical community, have come up with strategies to kill cancer, and one of them is to process in vitro T cells, perhaps CD8 positive, perhaps CD4 positive, such a way that they have chimeric T cell receptors, which will then allow them to react to multiple neoantigens from cancers and evade the cancer's production of, for example, programmed death ligands and other molecules which would turn down the T cell activation proliferation.

Remember all of that, I'm sure.

And that goes all the way back to low-density lipoprotein receptor.

And the metabolic reprogramming has to do with lipid metabolism.

In the tumor and micro, uh, microenvironment, myeloid cells have been detected to alter carbon source for ATP synthesis, so for example, and also lipid biosynthetic and lipid degrading pathways.

Okay? So an antigen-specific CD8 positive T cell that is introduced either into vaccinated or tumor-bearing mice receiving adequate equivalent amount of antigen stimulation.

When you study the CD8 positive T cells, your C- CTLs, your cytotoxic T lymphocytes, that are isolated from those tumors, what do you see? You see significantly lower cholesterol than those from vaccinated mice.

So you can kind of think of the CD4 or helper T cell as what its name says, as a helper, right? It's got all these different functions that kind of tie together different bits of the immune system.

On the other hand, you have what are known as CD8 positive T cells or cytotoxic T cells.

And this is the second kind of T cell I want to talk about.

And these CD8 T cells bind to MHC class 1 molecules.

And remember, these are the glycoproteins that are able to bind to intracellular antigens.

And essentially their role is to bring these antigens to the surface of the cell and kind of let the cell say, hey, I'm infected with this bad pathogen.

You know, come help me take care of this pathogen.

Come kill me, whatever this T cell has to do to get rid of this pathogen.

So what I'm saying basically is if you come to Authentic Biochemistry Podcast, that as a biochemist, I acknowledge what I just stated there as fundamental truth, and that's what science, research science, is hopefully completely devoted toward.

When we think about cholesterol metabolic programming in tumor-infiltrating CD8 T cells, remember that we were asking a question from the papers that were published.

Is there adequate amounts of cholesterol genesis in these cells? Because we know cholesterol is necessary universally for these particular T lymphocytes to function to kill tumors.

Or do they require, do these cells require cholesterol coming trafficked from LDL, low-density lipoprotein, docking to its specific receptor and unloading cargo, including amongst other lipids and protein, cholesterol itself.

So that paper that we basically finished last lecture, which was Saturday, discovered that low-density lipoprotein receptor transcription level was decreased in cytotoxic T lymphocytes.

Those are CD8 positive T cell specificity there, a terminal differentiation therein, when they infiltrate into tumor microenvironments.

Do you understand? The tumor microenvironment alters the transcription of the low-density lipoprotein receptor in the cytotoxic T lymphocytes that are there to kill the tumor.

And so the reduced surface level of the receptor in those tumor-infiltrated cytotoxic T lymphocytes was evaluated via a several cytometric analyses.