a bonobo humanity?

It’s still early days, but gene-therapy modifications of bone marrow stem cells may be the solution to many haematological malignancies

Peter Doherty, An insider’s plague year

something like…

Canto: So we’re going to try and educate ourselves with the help of all these videos out there on the immune system, with hopefully occasional references to the SARS-Cov2 coronavirus. And we’re not going to reference all these videos and websites because it’s just too time consuming and nobody else is going to read this stuff, it’s just for ourselves, mostly much.

Jacinta So in a vid about T-cell development (and they’re a product of the adaptive immune system) we hear that T-cells are produced in the red bone marrow. Why red? 

Canto: Bone marrow comes in 2 types:

Red bone marrow contains blood stem cells that can become red blood cells, white blood cells, or platelets. Yellow bone marrow is made mostly of fat and contains stem cells that can become cartilage, fat, or bone cells.

Jacinta: So it’s not about red bones. So stem cells are like stems, green shoots that can develop into all sorts of different plants?

Canto: Yes and so you can imagine the potential, if we can induce them to specialise in ways that we want. Homo deus and all that. My brief research tells me that they’re found all around the body, not just the marrow. But it doesn’t tell me how they came into being. And there are apparently different types, as in ‘blood stem cells’. So these particular cells are pushed out into the world via sinusoidal capillaries…

Jacinta: Capillaries are the narrowest of blood vessels, I know that much…

Sinusoid capillaries allow for the exchange of large molecules, even cells. They’re able to do this because they have many larger gaps in their capillary wall, in addition to pores and small gaps. The surrounding basement membrane is also incomplete with openings in many places.   

Canto: I must say that the number of high-quality, comprehensive videos on immunology, e.g. on YouTube, is such a boon. The comments say it all, ‘if only I had this info available when I was doing my PhD’ etc etc. So back to T cells. They move, I think as precursor T cells, to the thymus, via those capillaries. The thymus is a small gland near the top of the lungs (in the thoracic cavity) which is an essential component of the lymphatic system, itself a part of our general immune system. 

Jacinta: It’s described as a primary lymphoid organ – at last I’m going to find out more about lymph! I hope. So the thymus is where T cells develop, and the red bone marrow, another primary lymphoid organ, is where B cells develop. 

Canto: And B cells are a ‘type of white blood cell that makes infection-fighting proteins called antibodies’. Whereas T cells fight infections more directly as well as doing a lot of signalling…

Jacinta: Interesting thing about the thymus – it functions mostly through early childhood and adolescence, after which it atrophies, its tissues becoming fibrous and non-functional. So its role in T cell maturation occurs in our early years. 

Canto: The thymus secretes different types of chemokines, or chemotactic agents (thymosin, thymotaxin, thymopoetin and thymic factors) which are somehow able to pull these undeveloped T cells in the right direction. This process is called chemotaxis. 

Jacinta: A chemical taxi system, how cute. So we mentioned the two primary lymphoid organs, and there are secondary lymphoid organs – the lymph nodes (found in a number of bodily locations) and the spleen (on your left side, just around the bottom of your rib-cage). Just on chemokines – we’ve heard of cytokines, and the worrisome ‘cytokine storm’ that was oft-mentioned during the Covid period. Chemokines are a subset of these cytokines, which are –

‘an exceptionally large and diverse group of pro- or anti-inflammatory factors that are grouped into families based upon their structural homology or that of their receptors. Chemokines are a group of secreted proteins within the cytokine family whose generic function is to induce cell migration’.

Canto: So now we’re looking at these precursor T cells arriving at the thymus. So the thymus has a heap of thymic, epithelial cells which secrete the above-mentioned chemokines, which stimulate certain genes within the T cells to produce two enzymes (proteins), RAG1 and RAG2 (RAG stands for recombination activating gene – the genes encode the proteins). These are types of recombinase…

Jacinta: Think of genetic recombination, or mixing:

Recombinases are a family of enzymes having functional roles in homologous and site-specific recombination. It’s an event in organisms that involves DNA breakage, strand exchange between homologous segments, and ligation of DNA segments using DNA ligase.

Canto: So in this T cell context the gene ‘shuffling’, as it might be called, produces different protein types to deal with different antigen types. For example they produce T cell receptors (TCRs) designed to recognise and ‘receive’ differently-shaped antigens.

Jacinta: So getting back to those chemokines, they’re inducing other genetic activity to produce CD (cluster differentiation) proteins, of which there are various conformations, such as CD4 and CD8. These proteins form on the outside of the T cells, where they, hopefully, bind to MHC (major histocompatibility complex) proteins on the thymic cells. And of course there’s always more complexity – ‘a human typically expresses six different MHC class I molecules and eight different MHC class II molecules on his or her cells’. For now just think MHC-1 and MHC-2. Recognition of the appropriate MHC molecules by the CD4 and 8 proteins is called ‘positive selection’. If positive selection doesn’t happen the T cells will die (apoptosis).  

Canto: The next step, assuming T cell survival, has to do with the previously-mentioned TCRs. The MHC molecules on the thymic cells carry a ‘self peptide’, and just to show how complex and relatively recent our immunological knowledge is, here’s a quote from a Pub-Med abstract from late 2001:

Twenty years ago, antigenic and self peptides presented by MHC molecules were absent from the immunological scene. While foreign peptides could be assayed by immune reactions, self peptides, as elusive and invisible as they were at the time, were bound to have an immunological role. How self peptides are selected and presented by MHC molecules, and how self MHC-peptide complexes are seen or not seen by T cells raised multiple questions particularly related to MHC restriction, alloreactivity, positive and negative selection, the nature of tumor antigens and tolerance.

So, if we could imagine ourselves as upper-class kids who entered university in the late 70s, (instead of working in factories or bludging off the dole as we were doing), none of this would’ve been known to anyone and we could’ve helped make the breakthrough…

Jacinta: Woulda-coulda-shoulda. Back again to those T cell receptors (TCRs), which apparently are not supposed to recognise or connect with the thymic cells’ self or antigenic peptides, as that would lead to auto-immune complications. So they’re ‘designed’ for that purpose, so that they don’t recognise those peptides, and don’t connect with them. This is called negative selection. If for some reason recognition does occur, apoptosis will result. That process occurs by the release of FAS (aka APO-1 or CD95 – don’t ask) from the thymic cell to a receptor in the T cell. 

Canto: So, up to this point, if the T cell has come through alive, it’s TCR-positive, CD4 positive and CD8 positive. Its CD4 molecule may interact fortuitously with the thymic cell’s MHC2 (but the CD8 doesn’t interact with MHC1). In that case, there will be gene up-regulation of the cell’s CD4 molecules and down-regulation of CD8. That’s to say, CD4s will increase and CD8s will reduce, and it will present other TCRs. This turns it into a ‘T helper cell’. On the other hand, if the cell’s CD8s connect with the MHC1, there will be up-regulation of CD8, down-regulation of CD4, converting it into a cytotoxic T cell. Some  of these helper and cytotoxic T cells can further develop into T regulatory cells, aka T suppressor cells, important for auto-immune disease suppression.  This is promoted by molecules such as CD25 and interleukin 2. 

Jacinta: Ok that’s enough head-spinning for one post, except perhaps just to say that interleukin 2 is ‘a protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible for immunity’. And we might find out more about what ‘cluster differentiation’ actually means….

Reference

This almost all comes from one video:

Immunology | T- Cell Development, Ninja Nerd