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• W2531368876 abstract "The T in T cells denotes thymus-derived, for it is in thethymus that stem cells from the bone marrow matureinto functional T lymphocytes capable of defensiveaction against environmental antigens. Unlike a modernindustrial production line, however, the thymic factoryrejects most of its products as substandard - thesuccess rate is even worse than for junior faculty apply-ing for government research grants. This might be seenas evidence of gross inefficiency, or alternatively asexquisitely specific discrimination. Whatever one's pointof view, only a few percent of aspiring T cells makeit into the real world of the blood, lymphatics andconnective tissue that make up the peripheralcirculation (Fig. 1).An individual T-cell's fate is ultimately determined bythe affinity of the antigen receptors (also known asT-cell receptors) it bears on its surface for one of theclass I or class II molecules of the major histocompati-bility complex (MHC) that are expressed by the antigen-presenting cells of the thymus. But other factors -including the cell-surface densities of T-cell receptorsand MHC molecules, and the presence of various othercostimulatory and adhesion molecules - build on thesimple affinity of the T-cell receptor-MHC interactionand modify the overall strength of the connectionbetween a T cell and an antigen-presenting cell todetermine the functional outcome.In the 1970s, experiments using chimeric mice firstrevealed the influence on T-cell specificity exerted byMHC molecules of the thymus. Perhaps it was compari-son with their own experiences at institutions of learn-ing that led immunologists to use 'education' todescribe what happens to T cells within the thymus.Later on, the utter unsuitability of the term dawned:nothing new was ever imparted to the 'students', few ofthem graduated and an even smaller number went onto do something useful - most just hung out. The pro-cess in the thymus began to be seen more as a siftingout of the aggressive, combined with abandonment ofthe weak and elimination of the downright awkward.Eventually, the term 'thymic selection' was adopted.To summarize current opinion, a T cell commits suicideif its receptor interacts too strongly with any one ofthe class I or class II molecules of the MHC found onthe surfaces of thymic antigen-presenting cells.Alternatively, if its receptor binds feebly to all thevarious MHC molecules present, the T cell is ignoredand, through lack of attention, fades away. Betweenthese two extremes, both of which lead to negativeselection, are the T cells with receptors that have justthe 'right' affinity for one of the MHC molecules. Suchsplendid cells are rewarded with signals initiatingfurther differentiation to ensure their access to theperiphery, where they form an elite of positivelyselected T cells (Fig. 1).Ever since the first informative experiments by Bevan [1]and Zinkernagel and colleagues [2], there has beenresistance to the idea of positive selection.Conceptually, the debate was not dissimilar from thatconcerning the respective roles of natural selection(positive) and purifying selection (negative) in the evo-lution of proteins. In the way such controversies go,proving the case has been perceived as requiring moreevidence, examples and publications than might other-wise have been thought decent. Now, however, thereseems to be agreement as to the reality of positiveselection.Lately, experiments making the case for positive selec-tion have involved mice that are either transgenic or'knocked-out' for particular T-cell receptor or MHCmolecules [3,4]. Such experiments first demonstratedthat expression of a particular MHC molecule in thethymus is a necessary prerequisite for the production offunctional T cells responsive to foreign antigens pre-sented by that MHC molecule. Most humans express atotal of six different class I MHC molecules (two allelicproducts from each of the loci HLA-A, HLA-B and HLA-C) and six different class II molecules (two allelic prod-ucts from each of HLA-DP, HLA-DQ and HLA-DR). Theprinciple of positive selection would therefore predictthat all the functional T cells of an individual should bedivisible into twelve subsets, each consisting of those Tcells selected by (and therefore expressing receptorsresponsive to a single HLA molecule). Furthermore, thesix T-cell subsets selected by the class I moleculeswould be those bearing the CD8 coreceptor, whereasthe six subsets selected by class II molecules would bethose bearing the CD4 coreceptor.A role for peptideMore recent experiments suggest that a further divisionof T-cell subsets results from the heterogeneity ofpeptides bound by molecules of a particular class I orclass II type [5,6]. The study by Hogquist et al. [6] of aparticular class I MHC molecule serves to open up thisnext layer of immunological complexity. Expression ofa class I MHC molecule at the cell surface, in a" @default.
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• W2531368876 modified "2023-09-23" @default.
• W2531368876 title "Accentuating the positive T cells can be selected positively or negatively by the same peptide under different conditions. The type of selection depends on the avidity of the interaction between the T cell and the antigen-presenting cell." @default.
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