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thymic location subcapsule / outer cortex outer / inner cortex medulla

Figure 2 Schematic diagram of T cell developmental stages in the mouse thymus. Immature T cells undergo various maturation steps which can be followed by the expression of the cell surface markers listed in the diagram. Note the relative cell size at different stages and the transition steps which are associated with significant cell proliferation.

Export to periphery

Export to periphery

Figure 3 Positive and negative selection in the thymus. Immature CD4"8~ 'double-negative' (DN) cells under the capsule proliferate and differentiate into CD4+8+ 'double-positive' (DP) cells expressing a low density of the c*(3 T cell receptor (TCR). A small fraction of DP cells express TCRs that have low but significant binding affinity for peptides bound to self MHC class I and II molecules displayed on cortical epithelial cells. These DP cells undergo positive selection. This process rescues DP cells from death and results in the cells migrating into the medulla and maturing into either CD4+8 or CD4~8+ 'single-positive' (SP) cells. In the medulla, SP cells encounter antigen-presenting cells in the medulla, such as dendritic cells (DC) and macrophages (M0). These cells display MHC-bound self antigens entering from the bloodstream, and any T cells with overt reactivity for these antigens are deleted in situ (negative selection). As the result of positive and negative selection, only a very small proportion of total thymocytes (1-2%) are exported from the thymus; the remainder of the cells die within the thymus.

mediated by the a|3 TCR and is aided by CDS or CD4 molecules. These two molecules act as corecep-tors by binding to nonpolymorphic epitopes on MHC class I and class II molecules, respectively. Thus, if the T cell is recognizing a peptide bound to class I, this binding is aided by CD8 molecules. Such binding stabilizes CD8 expression but leads to down-regulation of CD4, with the result that the cell differentiates into a mature CD4~8+ cell. Conversely, positive selection to peptide/class II complexes is aided by the CD4 coreceptor and leads to differentiation into CD4+8" cells.

The range of self peptides controlling positive selection is still unclear, but weak (antagonist) peptides seem to be particularly important. Most of these peptides are probably derived through breakdown of various intracellular proteins. Antagonist peptides may be particularly suited to provide the weak signaling required for positive selection. This level of signaling is sufficient to induce differentiation but fails to cause cell division. As discussed later, strong TCR signaling of CD4+8+ cells is injurious and leads to rapid death (negative selection).

Positive selection involves only a very small fraction of CD4+8+ cells, i.e. 2-4%. The vast majority of DP thymocytes (>95%) have no binding specificity for the particular self MHC molecules expressed in the thymus and these cells die rapidly from 'neglect'-. Death of these cells involves apoptosis, and special staining techniques reveal that apoptotic cells are rapidly cleared by adjacent macrophages. At face value the fact that the vast majority of thymocytes are doomed to die in situ seems wasteful and inefficient. However, this widescale destruction of immature T ceils reflects the need to select only those cells that are equipped to function optimally in the extrathymic environment, i.e. to respond to foreign peptides presented by the particular self MHC molecules of the individual. The TCR repertoire of CD4+8+ cells is presumed to be very broad and to encompass reactivity for all of the different MHC molecules expressed in the species as a whole. In any one individual, however, the range of MHC molecules is very small, with the result that specificity for these self MHC molecules is limited to a tiny fraction of DP cells. The fact that only a small number of DP cells undergo positive selection can thus be viewed as a reflection of the extent of MHC polymorphism.

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