Further notes about the morphostasis concept – split files

(26) Thymic tolerance

The following is adapted (changes mostly italicised) from a response I recently submitted to a discussion in ResearchGate .

[Start] It is important to keep the initial subject of this discussion group clearly in mind and anything I write, now, must have a clear bearing on it. Metaphorically, the Red Queen hypothesis implies that we are running simply to stay still. When this is applied to species vs species competition it is all too easy to assume that the primary goal is to learn, on the one hand, new methods to recognise and kill the opposition and, on the other, to devise new means of better cloaking your activity. However, you can win a war by starving your opponents out of resources; and of all strategies, this would be the best basis on which to start. Other mechanisms can then be bolted on as adjuncts. To me, the real Red Queen process lies with entropy; an animal looks very stable and organised but the gradient of entropy strongly favours disorganisation unless integrity is actively maintained. This is very much a process of continually running simply to stay still. To maintain order in a world where entropy favours disorder, we must continuously find energy sources, building materials (that themselves have a tendency to disperse evenly throughout the wider environment) and a niche environment where this can be achieved. So, a major problem arises once more than one species competes for the available resources whenever they occupy an overlapping niche. All subsequent evolution (unless extinction comes to one of the parties involved) becomes a compromising trade off and a continual vying with opponents for these resources. Resources are absolutely central; the management and the protection of them is a major goal of every organism that has ever existed since life began.

Now, the extant view, pre–1994 was, for almost every immunologist, that the immune system discriminated self from non–self. (It was assumed, without deeper analysis, that antigens were the basis on which this discrimination was made). Self (an array of different antigens) was learnt in utero by the elimination of all self(–antigen) reactive T–cells (and B–cells/antibodies) and the thymic system generated a population of immune cells that were ready and able to (aggressively) zap the rest. QED – immunity's overarching mechanism and purpose was explained.

Why do I think that the thymic processing of T–cells is relevant to the Red Queen hypothesis? What justifies many words – here – on this subject? Well, an alternative and newer view of immune function is that it is driven by the phagocytic/inflammatory processes in an animal. Inflammation identifies all sorts of debris. It listens out for the cries of distressed static tissues and responds vigorously. First, it delivers a deluge of phagocytic cells that look for anything that has the signature of debris, represents openly available energy or contains useful resources (micro–organisms included here as they represent the amoebocyte's primeval banquet). Included in this debris are membrane intact globules of apoptotic debris and spilt cytoplasmic debris (a nice meal for bacteria). It is important to mop them up, re–assimilate them, deny interlopers access to them and then, in the resolution phase, to restore order.

All the evidence, for me, points towards the Mhc system as a process for managing debris (both intra– and extra–cellular) and then presenting this debris as peptide fragments attached to Mhc molecules at the cell surface. The NK cell system probably uses the same process. I suspect it learns to recognise self Mhc associated with some pretty standard physiologically usual intracellular turnover products that are typical of healthy self cells. And it is on the alert for a sudden change from this pattern (frequently such a change is an indication of a viral invasion). So new viral peptide debris may suddenly populate the peptide grooves and this robs the cell of its "healthy self" identity. Interestingly, the second "cull" of T–cells in the thymus is of a population of cells very similar to this NK specificity and it is remotely possible that some of these are promoted into an NK like activity rather than being totally (clonally) eliminated. Whatever, this second filtering (culling or diversion into an alternative activity or disabling) is of T–cells strongly reactive with an Mhc+healthy–self peptide signature – of this "healthy" sort.

The first filtering in the thymus – and this filters out the large majority of incident precursor T–cells – is of those cells that have no affinity for self Mhc. I guess that this first filtering is NOT preoccupying itself with the Mhc groove. These cells – 95% or more of the incoming precursor T–cells, die by neglect and produce a veritable mountain of apoptotic debris that is efficiently and silently (no inflammation) cleared and re–assimilated.

However, it is becoming eminently clear that naïve T–cells (those that have escaped thymic filtering) do not come armed with a preformed intention to "zap" nonself. They remain naïve and available to be committed to tolerance (T–reg) or aggression (cells like Tc and Th); but this commitment is made in the context of the inflammatory environment in which they are encountered in the periphery. Precursor T–cells (fresh from the marrow and so far not filtered in the thymus) continue to be produced throughout life.

What this all means is that precursor T–cells are selected for self Mhc reactivity (perhaps excluding the peptide groove). The majority (no affinity) are redundant and die of neglect through apoptosis. Of the remainder, those that respond strongly to locally presented Mhc molecules (presumably loaded with healthy self / physiologically normal and common peptides) are in some way rejected from the pool of final responders. The remaining pool of selected T–cells have a lower affinity for the locally displayed thymic Mhc molecules. These become naïve – uncommitted – T–cells. The massive apoptosis that occurs regularly in the thymus probably leads to a substantial proportion of these naïve T–cells being committed, in the thymus, into T–reg cells and these actively suppress "self" reactivity once released into the circulation. The remaining naïve T–cells that escape the thymus circulate and are ready to be committed – on the basis of messy or tidy debris – into T–aggressor or T–suppressor cells. So thymic tolerance may well be pretty much the same process as peripheral tolerance.

See THIS ARTICLE for a good summary of thymic processing and the involvement of T-reg cells.
[I have now added two more references (by Legoux FP et al and by Davis MM) in the "Other interesting references" section of the Supportive references.]

The upshot is that there is a strong argument for saying that the system is a debris management system. "Foreign" does not guarantee aggression – as many pathogenic organisms have discovered for they encourage apoptosis to get themselves tolerated. And it is fortunate that this is possible in our guts. Likewise "self" does not guarantee tolerance. When "the mess keeps coming" a persistent and substantial provocation is eventually able to overcome the T–reg down regulation of inflammation. Both thymic and peripheral tolerance may be overcome – but it is hard to provoke this. Adjuvant arthritis, however, shows how potentially easy it is to overcome it with a concerted attack of "mess". [End]

The dominant, extant, view of thymic processing is that self reactive T–cells die by neglect. Is this view a true fact (a confirmed observation) or an assumption? Many precursor T–cells do die in the thymus as evidenced by their massive apoptosis in that organ. But, are these all self reactive T–cells? Or are they T–cells with no reactivity to unloaded or loaded self Mhc molecules (Mhc groove loaded with peptides)? The simplest explanation would be that precursor T–cells that "recognise" Mhc molecules (with low affinity) may lead on to the production of a population of naïve T–cells that are then ready to be committed to suppression or aggression when they encounter their appropriate Mhc/peptide epitopes in an appropriate melieu. One might anticipate that high affinity precursor lymphocytes are enrolled into a T–nk like activity rather than being deleted. These are points to be firmly established but the early evidence is favourable to at least some of these proposals. My guess is that the first filtering is to eliminate precursor T–cells that have no affinity for unloaded self Mhc molecules. The second filter is to divert those with high affinity for self Mhc and common degraded self peptide into an NK or T–nk profile. The last filtering is to select for the rest, those with lower affinity for self Mhc molecules (whose affinity may increase on peptide loading). Now, all the apoptotic debris in the thymus can commit appropriately reactive naïve T–cells into tolerance and then release this mix of regulatory (tolerant) T–cells and continuing naïve T–cells into the blood stream and thus the periphery. This makes much more sense and leaves central and peripheral tolerance as similar processes. These conjectures are "suddenly" allowed by adopting an alternative perspective to the microbe killing and immunologically aggressive system that older views have assumed.

I suspect that a major reason that the conventional perspective stalls (in my view, of course) is that the conventional self/non-self epitope perspective regards the T-cells (that emerge from the thymus into the periphery) to be committed to attacking non-self epitopes. I contend that the T-cell emigrants that emerge from the thymus are either already committed to tolerance (so called central tolerance) or do not have a committed effector role; they are primed ready to categorise their respective epitopes into "worthy of aggression" or "worthy of tolerance" but remain uncommitted until the epitope is encountered. This categorisation is "chosen" during their contextual encounter with the respective epitopes (on the basis of a controlled-shutdown or catastrophic-death association).

TEST PROPOSAL: I guess that it should be possible to to devise experimental procedures to explore the effect of necrosis within the foetal thymus. This might alter the responses evoked to selected epitopes. Should we be able to prove that particular forms of uncontrolled cell shutdown evoke aggressive immune responses in utero, then this would go a long way towards supporting the proposal that {controlled cell shutdown} versus {catastrophic cell death} modulates the balance of tolerant to aggressive immune responses – even in the foetal thymus. This may well be already supported by observational data or "natural experiments" that I am not aware of.

[I have now added two more references (by Legoux FP et al and by Davis MM) in the "Other interesting references" section of the Supportive references.]