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# Are self-recognizing Thymus lymphocytes more central than people consider?
These days, lymphocyte receptors are believed to use instructive theory to increase affinity for foreign-antigen. It is information-theory wise a lot easier to rule out self-antigen, than to recognize specific non-self antigen. Probabilistically, 9-mer peptide fragments have > 10^11 combinations (Brusic, 1999), but self-9-mer peptides < 10^8 (Brusic, 1999), at least 10^3 easier to rule out self and probably closer to 10^4. Once self is ruled out, T-cells too could use affinity maturation. And cytotoxic, specialized T-cells develop. People say T-cell receptor does not use affinity maturation but the same was said for instructive theory in general from 1960s until pretty recently I think. If an antigen presenting cell (APC) has displayed a peptide fragment on MHC that has been inspected by a threshold of 10^n self-recognizing lymphocytes, and estimated the antigen to be foreign, it could very easily order T-cells to initiate affinity maturation-like development of T-cell receptors specific to that antigen, and have a clone of T-cells that are very good at hunting down the invader, and also very good at helping B-cell to initiate affinity maturation.
The work put in by the Thymus is said to be mostly about removing self-recognizing T-cells. But, keeping them around provides an extremely useful tool. The dogma is that keeping them around is dangerous, because they might switch to a non-self recognizing type but then have a T-cell receptor for self-antigen, and then there is some memes about how weakly self-recognizing can at the same time still be allowed, and these are then assigned to the neglected and marginalized (Corthay, 2009) suppressor or regulatory T-cells. This dogma that self-recognition is dangerous, should be central to the exploration of a more central role of self-recognizing Thymus cells. If the dogma is wrong, then my intuition is right. There is also a perfectly logical reason for a hypothetical false dogma to have developed, the risk of auto-immune disease being very real, and the threat associated with self-recognition in a world that does not tolerate independent thought.
Scalability-wise, a self-centered Thymus system is extremely efficient. The number of self T-cells necessary to verify an antigen as foreign, is proportional to the number of self-antigens that MHC can present. MHC molecules are said to form highly promiscuous peptide-binding clefts (Brusic, 1999; 2004). The number of peptides that can bind each individual HLA class I molecule was estimated at between 1000 and 10000 individual sequences (S. Stevanovic via Brusic, 2004), or up to 100000 (Sem, 2007), and and more than 2000 peptides for class II allotypes (Meydan, 2013), and each individual expresses up to six HLA class I molecules and at least that many HLA class II molecules. The so-called highly promiscuous peptide binding groove is still only capable of binding a very small fraction of all possible peptide fragments, and the fraction of self-to-foreign antigen is < 10^-3 (Brusic, 1999), so out of the 10000 or 100000 possible sequences a MHC molecule can bind, only 1 to 10 (Brusic) or 100 (Sem) are self-antigen.
The extreme efficiency of a self-centered Thymus system is that the < 10^-3 proportion of MHC antigen that are self-antigen, can be validated with 10^n redundancy by total_MHC_self_antigen * 10^n randomly sampled "self lymphocytes". T-cells are known to constantly swarm the body, millions passing through lymph nodes per hour (Hall, 1967), and if there is any validity to Brusic or Sem's estimates of MHC promiscuity, that self-antigen per MHC allele are a few dozen or a few hundred, they can be used to estimate this threshold. Mathematically, in a population of x objects, where n different types of objects exist, the probability of covering all n types probably increases non-linearly and at some multiple of n, enough objects have been sampled to satisfy a desirable probability threshold. If this threshold is 100, total self lymphocytes needed to audit antigen is between 100 and 10000, per allele (and six alleles in total), depending on Brusic or Sem's estimates.
The alternative, to find the T-cell clone specific to a foreign-antigen, that have been selected by somatic mutation, never encountered the antigen before, and not undergone clonal expansion, is 10^11 possible 9-mer peptides. That MHC is only able to present a fraction of these, cannot inform the T-cell receptors that cannot know what peptides this fraction is. 10^11 possible foreign antigen in a population of 10^12 T-cells, leaves 10 T-cells per antigen. Probabilistically, each antigen has to be scanned by 10^11 T-cells to reach same conclusion as a few thousand "self lymphocytes".
# Synapses
Brusic, V., & Zeleznikow, J. (1999). Letters in Peptide Science, 6(5/6), 313 324. https://doi.org/10.1023/a:1008948124145
Brusic, V., Bajic, V. B., & Petrovsky, N. (2004). Computational methods for prediction of T-cell epitopes a framework for modelling, testing, and applications. Methods, 34(4), 436 443. https://doi.org/10.1016/j.ymeth.2004.06.006
Corthay, A. (2009). How do Regulatory T Cells Work? Scandinavian Journal of Immunology, 70(4), 326 336. https://doi.org/10.1111/j.1365-3083.2009.02308.x
Sem, D. S. (2007). Spectral Techniques In Proteomics (1st ed.). CRC Press.
Meydan, C., Otu, H. H., & Sezerman, O. U. (2013). Prediction of peptides binding to MHC class I and II alleles by temporal motif mining. BMC bioinformatics, 14 Suppl 2(Suppl 2), S13. https://doi.org/10.1186/1471-2105-14-S2-S13
Hall, J. G. (1967). QUANTITATIVE ASPECTS OF THE RECIRCULATION OF LYMPHOCYTES; AN ANALYSIS OF DATA FROM EXPERIMENTS ON SHEEP. Quarterly Journal of Experimental Physiology and Cognate Medical Sciences, 52(1), 76 85. https://doi.org/10.1113/expphysiol.1967.sp001887