T cells undergo both positive selection for self MHC restriction and negative selection for self-tolerance by interacting with self peptide:self MHC complexes expressed on stromal cells in the thymus. An unresolved issue is how the interaction of the T-cell receptor with self peptide:self MHC complexes distinguishes between these opposite outcomes. First, more receptor specificities must be positively selected than are negatively selected. Otherwise, all the cells that were positively selected in the thymic cortex would be eliminated by negative selection, and no T cells would ever be produced. Second, the consequences of the interactions that lead to positive and negative selection must differ: cells that recognize self peptide:self MHC complexes on cortical epithelial cells are induced to mature, whereas those whose receptors might confer strong and potentially damaging autoreactivity are induced to die.
Currently, the choice between positive and negative selection is thought to hinge on the strength of self peptide:self MHC binding by the T-cell receptor, an idea known as the affinity hypothesis (Fig. 8.31). Low-affinity interactions rescue the cell from death by neglect, leading to positive selection; high-affinity interactions induce apoptosis and thus negative selection. Because more complexes are likely to bind weakly than strongly, this model explains the positive selection of a larger repertoire of cells than are negatively selected. Using T-cell receptor transgenic thymocytes, it was shown that variants of the antigenic peptide could induce positive selection in thymic organ cultures or in vivo. Peptide variants that induced positive selection had a lower affinity for the T-cell receptor than did antigenic peptide. How this quantitative difference in receptor affinity translates into a qualitatively distinct cell fate is still an area of active investigation. Many of the biochemical signals induced by low-affinity interactions are weaker or of shorter duration than those from high-affinity interactions. However, low-affinity interactions lead to sustained
Fig. 8.31 The affinity model of T-cell positive and negative selection. Random TCRα and β chain gene rearrangements generate a large pool of immature thymocytes expressing a varied repertoire of specificities. The T-cell receptors on many of these cells fail to have sufficient binding strength to the self peptide:self MHC complexes on thymic epithelium and so receive no signals. These cells die by neglect. Another fraction of immature thymocytes are positively selected because their T-cell receptors bind with sufficient strength to the self peptide:self MHC complexes on thymic epithelium to generate T-cell receptor-dependent survival signals. From this cohort of positively selected thymocytes, negative selection removes those thymocytes whose receptors have excessively strong reactivity to self peptides complexed with self MHC molecules (resulting in clonal deletion), thereby establishing self-tolerance of the mature T-cell population. A small subset of positively selected cells receiving signals slightly weaker than those inducing negative selection differentiate into regulatory T cells (Tregs), a process referred to as agonist selection.
activation of the protein kinase Erk, whereas high-affinity interactions lead to only transient activation of Erk, suggesting that differential activation of this or other MAPKs might determine the outcome of thymic selection. Indeed, experiments showed that developing T cells need to engage low-affinity ligands for more than 24 hours for positive selection to occur.
8-26 Self-recognizing regulatory T cells and innate T cells develop in the thymus.
Additional populations besides the conventional CD4+ and CD8+ α:β T cells discussed above emerge from the thymus; they are numerically minor but functionally important. Two of these subsets, the T cells (see Section 9-23) reg and the iNKT cells (see Section 6.18), have been well studied, and found to each have unique developmental requirements.