Expression of a single TCRb chain, DObWT and, even more markedly, DOb48A, reduces the number of different TCRa chains that can be positively selected, regardless of the selecting MHCII allele. Naïve CD4 T cells were isolated from the spleens (B6) or lymph nodes of mice expressing MHC b, f or s, single TCRb chains and heterozygous for expression of functional TCRa chains. Their expressed TCRa chains were sequenced and analyzed with species accumulation curves. Results were combined from 3 independently sequenced data sets from mice of each genotype except for those for H2s DObWT animals, which were combined from only two independently sequenced animals. Data are shown together with an estimate (bracketed) of the total numbers of different TCRa protein sequences present in the naïve CD4 T cells of each type of mouse. 

Expression of a single TCRb chain, DObWT and, even more markedly, DOb48A, reduces the number of different TCRa chains that can be positively selected, regardless of the selecting MHCII allele. Naïve CD4 T cells were isolated from the spleens (B6) or lymph nodes of mice expressing MHC b, f or s, single TCRb chains and heterozygous for expression of functional TCRa chains. Their expressed TCRa chains were sequenced and analyzed with species accumulation curves. Results were combined from 3 independently sequenced data sets from mice of each genotype except for those for H2s DObWT animals, which were combined from only two independently sequenced animals. Data are shown together with an estimate (bracketed) of the total numbers of different TCRa protein sequences present in the naïve CD4 T cells of each type of mouse. 

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... Majority of scTCR mutations are centred around the somatic driven CDR3, as germline fixed CDR1 and CDR2 loops are assumed to be invariant in a given individual. Even so, polymorphisms between individuals have been reported as evident from sequence data analysis (Marrack et al., 2017). The common belief is that germ line-encoded CDR1 and CDR2 loops are directed to increase the affinity of a TCR as they mainly interact with the MHC. ...
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... The germline-encoded CDR1/CDR2 regions of the TCRα and TCRβ variable domains are believed to contribute mainly to the basic interaction of TCR with MHC-II, modulating the binding angle of the hypervariable region relative to p-MHC (15,54). Previously, it has been reported that TRBV and TRAV segment usage is strongly associated with the expressed allelic variant of MHC-II (19,55,56). The observation that point substitutions in conserved stretches of amino acids in MHC-II alter TRBV and TRAV segment usage in CD4 cells but do not affect the CD4 + numerical count (25) provides further, direct evidence for preselection of TCR repertoires in MHC recognition. ...
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... Distinguishing between (2) and (3) in favor of near-self decreases the possibility of autoimmune reactivity (Burnet 1959;Forsdyke 2015. Thus, it is now generally agreed that there are "preferential selection and increased survival, in both the thymus and periphery, of T cells that carry specific CDR3 sequences that recognize self-antigens presented by MHC molecules" (Madi et al. 2017;Marrack et al. 2017). Albeit controversial, this appears to be mainly a somatic, nongerm line, selection process involving not only CDR3, but also CDR1 and CDR2 (Lu et al. 2019). ...
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The Standard model of T‐cell recognition asserts that T‐cell receptor (TCR) specificities are positively and negatively selected during ontogeny in the thymus, and that peripheral T‐cell repertoire has mild self‐Major Histocompatibility Complex (MHC) reactivity, known as MHC‐restriction of foreign‐antigen. Thus, the TCR must bind both a restrictive molecule (MHC allele) and a peptide reclining in its groove (pMHC ligand) in order to transmit signal into a T cell. The Standard and Cohn's Tritope model suggest contradictory roles for complementarity‐determining regions (CDRs) of the TCRs. Here, I discuss both concepts and propose a different solution to ontogenetic mechanism for TCR‐MHC conserved interaction. I suggest that double (CD4+CD8+) positive (DP) developing thymocytes compete with their αβTCRs for binding to self‐pMHC on cortical thymic epithelial cells (cTECs) that present a selected set of tissue‐restricted antigens (TRA). The competition between DPs involves TCR editing and secondary rearrangements, similar to germinal‐centre B‐cell somatic hypermutation. These processes would generate cells with higher TCR affinity for self‐pMHC, facilitating sufficiently long binding to cTECs to become thymic T regulatory cells (tTregs). Furthermore, CD4+ Foxp3+ tTregs can be generated by mTECs via Aire‐dependent and independent pathways, and additionally on thymic bone‐marrow derived APCs including thymic Aire‐expressing B cells. Thymic Tregs differ from the induced peripheral Tregs (pTregs), which comprise the negative feedback loop to restrain immune responses. The implication of thymocytes' competition for the highest binding to self‐pMHC is the co‐evolution of species‐specific αβTCRV regions with MHC alleles. This article is protected by copyright. All rights reserved.
... Moreover, approximately 40% of antigen experienced IgG class switched antibodies from healthy human donors were also shown to have autoreactivity 428 . TCR repertoire depletion additionally occurs during thymic selection, whereby CD8 + TCR repertoire size is inversely related to individual MHC diversity, causing an apparent tradeoff between MHC diversity and TCR repertoire size 101,429 . It is not known whether recognition holes exist entirely due to the presence of central and peripheral tolerance, or if specific amino acid combinations (sequence motifs) are capable of naturally evading immune monitoring. ...
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... 49 This has gained support from studies of the TCR segments (complementary determining regions 3; CDR3) that play a major role in determining TCR specificity. 50 Indeed, it is now argued that there is "preferential selection and increased survival, in both the thymus and periphery, of T cells that carry specific CDR3 sequences that recognize self-antigens presented by MHC molecules." 51 Thus, doubts regarding anticipation of vulnerable characters of future pathogens, 35 are fading. ...
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With the emergence of clonal selection ideas in the 1950s, the development of immune cell repertoires was seen to require the negative selection of self‐reacting cells, with surviving cells exhibiting a broad range of specificities. Thus, confronting a universe of not‐self antigens, a potential host organism spread its resources widely. In the 1960s the two signal hypothesis showed how this might work. However, in the 1970s an affinity/avidity model further proposed that, anticipating a pathogen strategy of exploiting “holes” in the repertoire created by negative selection, hosts should also positively select near‐self‐reacting cells. A microbe mutating an antigen from a form foreign to its host to a form resembling that host, should prevail over host defenses with respect to that antigen. By mutating a step towards host self, along the path from non‐self to self, it should come to dominate the microbe population. By progressive stepwise mutations, such microbes would become better adapted, to the detriment of their hosts. But they would lose this advantage if, as they mutated closer to host‐self, they encountered progressively stiffer host defenses. Thus, as described in the affinity/avidity model, positive selection of lymphocytes for specificities that were very close to, but not quite, anti‐self (i.e. “anti‐near‐self”), should be an important host adaptation. While positive selection affects both B and T cells, mechanisms are uncertain. Converging evidence from studies of lymphocyte activation, either polyclonally (with lectins as “antigen‐analogs”) or monoclonally (by specific antigen), supports the original generic affinity/avidity model for countering mutations towards host self. This article is protected by copyright. All rights reserved.
... The combined effort between experimental and computational immunology provided us with a new perspective to designing vaccines that will be effective across demographic boundaries. Previously, the extreme degree of polymorphism observed in the MHC posed limitations for the development of such a vaccine because the ability to trigger an effective T-cell response is partly determined by the MHC phenotype of the individual and different individuals have different MHC allele (Macdonald et al., 2001;Marrack et al., 2017). The MHC genes are the most polymorphic of all human genes, with more than 10,000 alleles known (as of Feb 2018), and are important in increasing the range of responses that different individuals can mount. ...