Posts Tagged ‘T cells’
immunity 2: MIT lecture – more on immunity and auto-immunity
So we’re looking at cell-mediated and auto-immunity in this second lecture. We see an image of listeria, an intracellular bacterium, pushing out the edges of the cell, so that it can move between cells without entering the extracellular space. Listeria is a food-borne bacterium which can cause severe intestinal illness. So think of a host cell with an intracellular pathogen, bacterial or viral, taking advantage of these cells to reproduce and spread. This is not good.
B cells, as described before, have an antigen receptor, initially on the plasma membrane, and sometimes secreted into the intracellular space, while T cells only have the membrane-bound form. In any case these antibodies are directed outwardly. How can a listeria-like infection, within the cells, be dealt with? This involves a process called antigen presentation, in which peptides – short sequences of amino acids – are presented and displayed on the cell surface, so that T cells, in this case, can observe what is happening within the cell. This involves another molecule previously mentioned, the major histocompatibility complex (MHC). There are two classes of MHC. Class 1 has a heavy chain – a long polypeptide – and a light chain. So, two polypeptides encoded by different genes. It has two Ig domains proximal to the plasma membrane – and it’s all inserted into this membrane – an integral membrane protein. Then at the other end, distal to the plasma membrane, is another structure, which, looking at its crystal structure, is a ‘beta sheet with two alpha helices’, shaped somewhat like a cup [a beta sheet is a common secondary structure in proteins, formed by polypeptide strands (beta strands) connected laterally by hydrogen bonds, creating a pleated, twisted, sheet-like structure]. Inside the cup is a peptide which displays some of its amino acids, away from the MHC molecule, for T cells to observe.
So these Class 1 MHCs are membrane proteins displayed on all nucleated somatic cells, and the peptides held by these MHCs are derived from the cytoplasm within the cell. They are loaded on to the MHC molecule, which is translated (using ribosomes and types of RNA) on the endoplasmic reticulum (ER), and its extracellular domain is initially present in the lumen (internal space) of the ER. Its peptides come from proteins in the cytoplasm. What happens to these proteins – including unfolded proteins and those that might be ubiquitinated [refers to a protein that has had ubiquitin, a small protein, covalently attached to it, often marking the protein for degradation or influencing its function or localisation – thanks AI, and it has of course dawned on me that this MIT course has followed on from earlier biochemistry learnin] – is that they’re processed by the proteasome [a large, cylindrical protein complex that degrades proteins tagged with ubiquitin, a process essential for maintaining cellular homeostasis and regulating various processes like cell cycle and protein quality control], which this lecturer describes as ‘a kind of shredder-like function for protein’, which cuts the proteins into peptides which can then be pumped into the ER lumen via a transporter, TAP…
The transporter associated with antigen processing (TAP) is a heterodimeric protein complex (TAP1 and TAP2) that transports peptides from the cytosol into the endoplasmic reticulum (ER), where they bind to MHC class I molecules, a crucial step in antigen presentation to cytotoxic T cells.from AI overview
From there they are loaded onto the class 1 MHC molecule. The source of these peptides is from proteins in the cytoplasm, processed by the proteasome. So now that a peptide-MHC complex has been created, it can then be trafficked to the plasma membrane of the cell, where the peptide will be displayed for T cells to observe. The types of T cell that look at these class 1 molecules are known as CD8+ T cells.
There are also class 2 MHC molecules, which have fundamentally different properties. Both molecules display peptides on the cell surface (antigen presentation), but the structure of MHC class 2 is quite different. Instead of a heavy and light chain, there are two chains of roughly equal size, and they’re encoded by different genes than the class 1 MHC. There are two Ig domains proximal to the plasma membrane, and at the end of the MHC molecule there’s a groove or pocket that holds a peptide (aka a peptide-binding cleft).
The class 2 MHC is expressed on a more restricted set of cells. They’re expressed specifically on specialised antigen-presenting cells, such as B cells and phagocytic cells [also known as phagocytes, they are specialised cells of the immune system that engulf and destroy foreign substances, pathogens, and cellular debris through a process called phagocytosis].
Phagocytosis is the process by which a cell uses its plasma membrane to engulf a large particle, giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is called a phagocyte.
Endocytosis is a cellular process where a cell engulfs extracellular material, forming an internal vesicle to transport substances into the cell. This process, which includes phagocytosis (cell eating) and pinocytosis (cell drinking), is essential for nutrient uptake, cell signalling, and defence against pathogens.
Dendritic cells (DCs) are crucial immune cells that act as sentinels, capturing antigens and presenting them to T cells to initiate adaptive immune responses, effectively bridging innate and adaptive immunity (from AI overview)
References
Immunology 2 – Memory, T cells & Autoimmunity, MIT OpenCourseWare, YouTube video
the immune system 1: introducing the adaptive immune system – MIT lecture
Just something to start with…
It was in 1796 that Edward Jenner created the first vaccine, using material from a cowpox sore on a milkmaid’s hand and injecting it under the skin of an eight-year-old boy. I’ve not been able to ascertain whether Jenner injected the material directly into the boy’s bloodstream. In any case this has been regarded as the world’s first vaccination, a term coined by Jenner (from vacca, Latin for cow). Variolation, using smallpox scabs inhaled by the patient, had been practised in Asia for centuries before Jenner, and was promoted in Britain by Mary Wortley Monagu earlier in the 18th century. Variolation was certainly effective, and for some time there was a dispute about the best treatment. In any case, what was being brought into action by both treatments was the adaptive immune system.
So now to MIT’s introduction to immunology course, presented by Adam Martin. He mentions, in his first lecture, that there are many levels of immunity, and goes on to describe two, innate and adaptive immunity. Innate immunity is ‘the first line of defence’, and acts immediately. Neutrophils, which are white blood cells, are part of this innate system, which is quite static and unchanging, involving a constant surveillance. Adaptive immunity is also known as acquired immunity – and its acquisition takes time.
The adaptive immune system is more specific than the innate. That’s why we need regular flu vaccinations, because flu viruses can evolve quite rapidly. These vaccinations are designed to combat or provide immunity to new strains of the virus.
There are two branches of adaptive immunity: humoral immunity, which is protein-mediated (the proteins are called antibodies). This type of immunity is called humoral because these antibodies are secreted into bodily fluids or humors (blood, mostly). The types of cells that produce these proteins, these antibodies (Ab), are called B cells, which are matured in the bone marrow. The other branch is cell-mediated immunity, which involves T cells, which are matured in the thymus gland, near the top of the lungs.
So far so simple, but next we’re shown a scarily complex chart showing the derivation of all these cells from hematopoietic stem cells – most of these cells comprising the innate system, but also the T and B lymphocytes of the adaptive system (and they’re called lymphocytes because they’re the primary cells found in the lymph). So, it’s important that we can trace the ‘tree’ back to its ‘roots’, the progenitor cells.
Both the humoral and cell-mediated immune system cells have antigen receptors, which recognise specific antigens (Ag). An antigen is any substance that creates/generates an immune response.
Antibodies – goodies; antigens – baddies.
So, the B cell antigen receptor is also called an antibody, and an immunoglobulin (Ig). Structurally, antibodies are proteins with a lipid bilayer, which represents the plasma membrane. Outside of this membrane is the exoplasm, and inside is the cytoplasm. (I’m a little confused here – this sounds like the description of a cell, not a protein). Anyway we’re describing a B cell, and the antibody (protein) can have a trans-membrane domain spanning the plasma membrane, and an exterior Ig domain. These domains are modular folds (polypeptide chains) that are separate from the rest of the protein, and are inserted into the cell membrane, with an N-terminus exterior to the cell and a C terminus within the cell. Each antibody protein has two long polypeptides, the identical ‘heavy chains’ of the molecule. They also have smaller ‘light chains’, and it’s all laterally symmetric. The external tips of these antibodies are what recognises and binds to the antigen.
Now to the T cell receptor (TCR). It’s very different, and simpler, structurally. It has two chains, alpha and beta, and fewer immunoglobulin repeats. The tip of this double chain interacts with the antigen.
The B cell’s receptor, or antibody, has different forms. Some antibodies have transmembrane domains and are anchored in the plasma membrane, but other forms lack the transmembrane domain and instead of being an integral membrane protein, they’re secreted into the blood. The membrane-bound form comes first, but as an infection progresses, the secreted form becomes dominant. The T cell receptor only has the membrane-bound form.
There are many different antibodies, and each given antibody will recognise a different antigenic structure. They can recognise small molecules, proteins, DNA, carbohydrates, lipids, etc. But apparently that’s the B cell’s antibodies. The T cell receptor is more restricted, recognising peptides – short sequences of amino acids – which are presented by the MHC complex (classes 1 and 2). More of that later.
Properties of the immune system. First, specificity – they can finely discriminate between molecules. This is of course essential to avoid the prospect of auto-immune diseases. So, how are such levels of specificity achieved? Well, it’s complex.
Looking at B cell antibodies again, with their heavy and light chains. There are different domains on the heavy chain that are either variable or (more or less) constant. And the same goes for the light chain, with the same lateral symmetry described above. So, looking at the amino acid sequence of the variable part of the antibody (protein) molecule, looking at its structure from N to C terminus …. (?)
By convention, peptide sequences are written N-terminus to C-terminus, left to right (in LTR writing systems) – [from Wikipedia, N-terminus]
Imagine taking these antibodies from the variable region of the chain and aligning them (their amino acid sequence) from N to C. Each is a different antibody (or heavy chain polypeptide) produced by a unique B cell. Then we consider the residue number…
The amino acid residue number refers to the spot in the linear chain where that particular amino acid is found. For example, the number 20 means that amino acid is 20th in the chain.
.. and how much each amino acid residue varies along the sequence. ‘So if we were to align antibody gene stretches like this’, and check out the variation, we could graph it as in the diagram:
The Y axis being the amount of variation, and the X axis is the residue number along the polypeptide sequence. So you see from this graphic that there are three regions of hyper-variability. These regions are also called complementarity-determining regions (CDRs). Apparently there are always three of them?
So what are these regions? We’re shown a crystal structure of one of them (both heavy chain and light chain), with an antigen attached, as well as a ribbon diagram with its CDR, which contacts the antigen. We’re next shown an Ig fold with three loops extending from it, which can bind to external particles. These IG loops vary in amino acid sequence and each tiny variation will affect the binding ability, or affinity to an antigen. So the key here is the CDR.
Each B cell expresses a unique antibody protein, with unique specificity, due to its unique sequence at the CDR region. To get more of a particular antibody, the cell that expresses it can be clonally expanded, creating monoclonal antibodies. Each of those B cells will have an antibody, or antigen receptor, with that same specificity.
So that’s the generation of specificity, but the generation of diversity is also vital for enhancing the immune system. How is this diversity achieved? There are millions of B cells that have unique antibodies, and there aren’t a million genes producing those cells – we have about 30,000 genes. The answer is somatic ‘reshuffling’ or recombination. We have a single heavy chain gene, and two light chain genes, for antibodies. They’re made up of multiple gene segments. Specifically, the parts that make up the variable domain are composed of gene segments that are shuffled during the development of the B cell to give rise to a diversity of proteins.
So we’re next shown a graphic headed, no doubt importantly, ‘the immunoglobulin gene contains multiple V, D and J segments – one of each needs to be brought together to form a functional antibody gene’. The graphic, which I won’t reproduce here, shows the human Ig heavy chain locus on the right. On the left is a variable (V) gene segment, containing 45 variable genes. There’s a diversity (D) segment next to it, containing 23 more of these genes, and then there are 6 joining (J) segments. All of these are distinct regions of the gene, the exon that encodes this variable region of the antibody.
So there are multiple V, D and J segments.To generate a functional antibody, one V has to be brought together with one D, which then has to be brought together with one J to create the heavy chain. So the next graphic has the heading ‘Rearrangement of genomic DNA is needed to put together a gene that encodes an immunglobulin’. It indicates that, for the light chain, only V and J gene segments are required, whereas the heavy chain also requires the D segments. Most of the cells in our body, and also in the germline at the earliest stage of development, have this arrangement. But during lymphocyte development a recombination event occurs which brings the two (V and J), or three (V, D and J) gene segments together. So, recombination at the heavy and light chain genes for the antibody.
This is all quite different from the recombination that occurs during meiosis and the formation of the gametes. That recombination occurs between homologous chromosomes, while this type brings together and deletes segments along one chromosome to bring these V and J segments together (intra-chromosomal recombination) to create an antibody protein. It’s called VDJ recombination, and is specific to lymphocytes, because during the development of B and T cells there is an induction of recombinases that mediate this recombination [?] In this case a recombination mediated by ‘recombination-activating genes 1 and 2’, aka RAG1 and RAG2. All this is lymphocyte-specific, and these recombinases mediate this rearrangement, bringing unique V, D and J segments together. The diversity derives from the fact that each segment has a unique sequence, coding for a unique amino acid sequence, and a distinct protein.
But the body derives further diversity from another process. When these segments are shuffled there is imprecision – nucleotides can be added or subtracted (deleted) when these segments are joined. This generates more amino acid diversity, called junctional imprecision. So we have imprecise recombination, leading to the insertion or deletion of nucleotides [the basic structural units of nucleic acids – RNA & DNA – consisting of a nucleoside and a phosphate group]. If there is a multiple of three nucleotides either inserted or deleted, the result is a functional antibody. A multiple of three is required, to avoid a ‘frameshift mutation’, because ‘a cell reads a gene’s code in groups of three bases when making a protein’. That’s the system upon which it operates – if you inserted/deleted a single nucleotide along the line you wouldn’t get a functional protein.
Another important thing – which happens not as a consequence of this recombination process, but of activating the T cell, which is that in addition to these variations, there’s also somatic hypermutation – an elevated mutation rate at the Ig locus, which increases further the diversity of the amino acid at these variable antibody regions. This is also known as affinity maturation, as it increases the affinity of the antibody for its antigen. Note that this is T cell-mediated.
So the immunoglobulin gene is not expressed until this recombination occurs. So this recombination leads to the expression of either the heavy chain or the light chain gene. This is because the enhancer is downstream in the gene, so by vanquishing the intervening sequence you bring the promoter within range of the enhancer, and the gene is expressed. It’s really quite romantic.
Remember though that there are two copies of these genes – paternal and maternal, so there’s another feature of this system – allelic exclusion. A B cell expresses only one antibody, so if both alleles are expressing, that wouldn’t be the case. With allelic exclusion, if you get a recombination event that leads to a functional antibody for one of your inherited copies of the gene, it suppresses recombination on the other allele, so you will only get one heavy chain and one light chain gene expressed per B cell.
So these junctions between V, D and J segments are found in the CDR-3 region, and are responsible for the high level of variability at the CDR or hyper-variable 3 region.
So the last feature to describe is ‘memory’, the ability to recall a previously experienced infectious substance. The immune system needs to be able to do this, and this is the principle behind vaccination. A vaccine will inject an attenuated or inactivated foreign agent into your bloodstream so that the immune system will be alerted to that antigen if/when it turns up in the system later.
Several ways in which this ‘remembering’ manifests itself, comparing a primary infection with a secondary infection, the adaptive immune system has very different responses. The primary response is a little delayed, taking between 5 and 10 days, while the secondary response is generally between 1 and 3 days. The magnitude of the response, the concentration of antibodies that are produced, is larger the second time around. And the antibodies themselves have become ‘better’. This can be shown by antibody affinity – how tightly the antibody recognises (and binds to?) the antigen. Antibody affinity (‘tightness’ of recognition) is measured as the dissociation constant for an antibody to a given antigen. The lower the number, the tighter the binding. For the primary infection the antibody affinity is weaker, on the order of 10 to the seventh molar in terms of KD [KD, or KD, is a quantitative measure of antibody affinity – ‘the equilibrium dissociation constant between the antibody and its antigen’], and the secondary infection generates antibodies that are functionally better, less than 10 to the negative eleventh molar (sub-nanomolar), a very tight interaction between two molecules. So, more and better. So from the first infection to the next, a type of B cell – a memory B cell – will express an antibody specific to the previously experienced antigen, because, due to irreversible recombination, this will be encoded in the genome. The memory results from VDJ recombination being irreversible, so those memory B cells will be there even if the antigen is not. These cells can be generated by vaccination.
So ‘effector functions of antibodies’. They can bind to a foreign substance, interfering with its functionality. Neutralisation, for example, which means preventing the antigen from entering cells. Also phagocytosis, recruiting phagocytes to internalise the antigen (e.g. a bacterium), and recruiting killing cells to kill cells.(natural killer cells).
The lecture ends with a story in the fight against breast cancer, a treatment based on a mouse monoclonal antibody. So, we can use antibodies from other species to generate treatments. One example is herceptin, which can be used as a treatment for HER2-positive breast cancer. It’s based on a mouse antibody which recognises the HER2 growth factor receptor, which is over-expressed in about 30% of human breast cancers. Researchers have engineered a human antibody with the mouse sequence at its complementarity-determining region. So you have a human antibody, which won’t be attacked or removed by the human immune system, but will recognise HER2, and recruit immune cells to HER2 positive cells, neutralising and possibly killing them. This is the possible therapeutic aspect of antibodies, whatever their source.
So ends the first lecture.
References
https://www.abcam.co.jp/primary-antibodies/kd-value-a-quantitive-measurement-of-antibody-affinity
on the lymphatic system and its clever cells, mostly
Activation of macrophage or B cell by T helper cell
Jacinta: So we’re focussing now on the lymphatic system, ‘clear water’ remember. A most misleading definition. So there’s this network of vessels, nodes and ducts….
Canto: What’s a node?
Jacinta: It’s a point of connection, or connections. In plants, a node is a point of branching, like with leaves.
Canto: Yeah I knew that. What’s a duct?
Jacinta: Don’t kid kid. It’s like a vessel, only, somehow different. Maybe bigger? Anyway, nodes go with lymph. There are over 500 of these lymph nodes throughout our bodies. The system does a lot of clean-up work, preserving fluid balance. It’s also much implicated in the immune system of course, and it’s involved in other stuff that’s quite hard to summarise, as you know.
Canto: Something from a reliable enough website:
The lymphatic system plays a key role in intestinal function. It assists in transporting fat, fighting infections, and removing excess fluid. Part of the gut membrane in the small intestine contains tiny finger-like protrusions called villi. Each villus contains tiny lymph capillaries, known as lacteals. These absorb fats and fat-soluble vitamins to form a milky white fluid called chyle. This fluid contains lymph and emulsified fats, or free fatty acids. It delivers nutrients indirectly when it reaches the venous blood circulation. Blood capillaries take up other nutrients directly.
Jacinta: Never heard of lacteals. Have heard of chyle, but don’t know much about it. So chyle contains lymph. But what’s lymph?
Canto: It’s a not-so-clear beige-coloured milky fluid containing lots of WBCs, especially lymphocytes, of course, and fatty stuff. Well, actually, that’s not lymph, that’s chyle. Or both… So there’s this lacteal system of the small intestine, capillaries for absorbing fats – well, actually transporting them… but we need to know what bile is, and emulsification, and lipase, and glycerides and esters, and no doubt much much more.
Jacinta: Well we’ve committed ourselves to learning about the immune system and associated processes for some ineffable effing reason, so let’s soldier on.
Canto: Okay, so bile has nothing to do with Trump, at least not in this context. Bile ducts are this network of tubes inside the liver – well actually there are intrahepatic and extrahepatic bile ducts. Bile itself is a fluid made and released by the liver, for breaking fat down into fatty acids. For ‘digesting’ fat, sort of. Not particularly relevant to the immune system, but it’s all interesting en it? And it can cause problems, such as chronic bile reflux. I suspect I’ve experienced bile reflux, though not chronically. I think it’s also called acid reflux, suggesting bile is a kind of acid.
Jacinta: Or maybe not. Here’s another one of those websites that know more than us:
Bile is composed of ingredients designed to digest fat. While it isn’t an acidic formula, it’s harsh on the sensitive linings of your stomach and esophagus. Chronic bile reflux can erode these protective linings, causing painful inflammation and, eventually, tissue damage (esophagitis).
Anyway, I’m not sure how we got from chyle to bile.
Canto: Right, back to chyle and lymph. Have you heard of lymphoedema? That’s a blockage of the lymphatic system, which causes tissue swelling, mostly in the arms and legs but possibly just about everywhere.
Jacinta: Yes, and things fall apart, the centre doesn’t hold. So let’s get back to lymph nodes and the cells they contain. Within lymph nodes there are germinal centres containing a lot of B cells, or B lymphocytes. These have receptors (B cell receptors) on their membranes which are IgD antibodies, all of which have different binding domains, due to genetic recombination, which allows them to deal with differently structured antigens. Once binding occurs, signals are sent to the lymphocyte’s nucleus, resulting in what’s called receptor-mediated endocytosis. The signalling response creates pseudopods and/or clathrins which pull the membrane inside.
Canto: Ok, sorry to be boringly predicable, what are clathrins?
Jacinta: They’re proteins, very ‘clever’ proteins, as so many of them are. They mediate endocytosis, which is essentially the surrounding and cutting off of extracellular material within the cell, creating a vesicle, called an endosome I think, which might be transported to further action sites. So this is happening within the B lymphocyte. We have this B cell receptor bound to a foreign antigen, and chromosome 6 of this cell then can produce a molecule (MHC2) to ‘fit’ the antigen and fuse it to the cell membrane. This has the effect of activating the B cell, carrying an MHC2 antigen-carrying molecule on its surface, and IgD antibodies. Of course I haven’t explained how the clathrins actually carry out this transformation, because I can’t but I believe it’s all been worked out.
Canto: Yes of course, and now our lymphocyte is an antigen-presenting cell. There are three types of such cells – B lymphocytes, macrophages and dendritic cells. However, the lymphocytes still need to proliferate to be effective, and this requires a stimulus. And so enter the macrophages. These have MHC2 molecules on their surface, bound to a specific foreign antigen, and they also have MHC1 surface molecules bound to a self antigen (as do all nucleated cells). The macrophage presents this MHC2 molecule with its antigen to a type of T cell, described as a’naive’ (i.e. non-specific) T helper cell. These helper cells will have, somewhere on their surface, specific protein molecules, called CD4, that ‘fit’ with the MHC2 molecules, and other specific molecules (T cell receptors) that fit with the foreign antigen. Specific TCRs fit with specific antigens. It’s all a matter of geometry, sort of.
Jacinta: These different types of TCRs are a product of genetic recombination, which involves RAG1 and RAG2 genes, and I can only guess that the R stands for recombination… Now these helper cells have CD3 signalling molecules inside (they send signals to the nucleus), and a molecule called CD28 on their surface. The macrophage has a protein, B7, which interacts with the CD28, and this protein interaction, called a co-stimulation reaction, sends a secondary signal to the nucleus – as opposed to the first, primary signal. This is known as co-stimulation.
Canto: So next, the macrophage starts secreting a molecule called interleukin-1, which binds to a specific receptor on the T helper cell, which results in a third signal to the nucleus, and activation of the T cell. The cell’s genes now produce interleukin-2, which can be secreted and will then bind to a receptor, as an ‘autocrine’, resulting in genes secreting another cytocrine, interleukin-4, and then interleukin-5. With all this, the T helper cell moves to another stage, becoming either a T helper 1 cell (stimulated by interleukin 12) or a T helper 2 cell (stimulated by interleukin 4). So, focussing on the T helper 2, it has activated interleukins 2,4 and 5, the latter two of which are especially important, after these cells have started dividing. That’s when those cytokines are produced.
Jacinta: We might be learning something. Now to the proliferation of the B lymphocyte. Interleukin 4 activates the B lymphocyte to start turning on genes for its proliferation – called clonal expansion. And they will have receptors (BCRs) specific to the foreign antigen. They’ll also have MHC2 surface molecules with exposed foreign antigens. They’re now ‘immuno-competent’ cells, and then, through the medium of interleukin 5, they will start differentiating. Some of these new types of cells are called plasma cells, which have a very prominent rough endoplasmic reticulum (RER), others are called memory B cells. Interleukin 5 and 6 stimulate plasma cells to produce and secrete antibodies specific to particular foreign antigens – or, rather, having variable regions that can adapt to and bind to those antigens.
Canto: And these antigens might be on the surface of bacteria, or not as the case may be. If they can bind to all the antigens on the bacterial (or viral) surface they can render it ineffective (neutralisation). Binding to freely circulating antigens can, however, cause problems. Such binding creates a precipitation reaction and this can be deposited in tissue resulting in a type 3 hypersensitivity. Don’t ask.
Jacinta: This is what United Staters call getting into the weeds, maybe. So that’s surely enough for now.
stuff on the immune system 2: T cells, mostly
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: