Thymically derived T cells are a subset of CD4+ T cells that function to main- reg tain self-tolerance. These cells arise from CD4+CD8+ thymocytes, as do conventional T cells. During their maturation, they upregulate the transcription factor FoxP3. T cell development also depends on IL-2 receptor signaling, a cytokine signal that is not required for the development of conventional T cells. The repertoire of T-cell receptors expressed on T cells is thought to be composed of receptors with high affinity for self MHC:self peptide complexes. Evidence supporting this conclusion comes from studies showing that some lines of TCR transgenic mice generate large numbers of T cells when the mice also express the antigen for this T-cell receptor. In addition, studies using mice expressing a fluorescent reporter that monitors T-cell receptor signal strength have shown that T cells express high levels of the fluorescent reporter, both during their development and after their export from the thymus, indicating that they likely express T-cell receptors with high affinity for self. This process of positive selection following high-affinity T-cell receptor interactions with self peptide:self MHC complexes has been termed agonist selection—in other words, agonist selection refers to interactions of a T-cell receptor with a self peptide:self MHC that would normally activate a mature T cell expressing that T-cell receptor.
A second specialized subset of T cells that develops from CD4+CD8+ thymocyte precursors is a lineage known as invariant NKT cells (iNKT cells), based on their expression of the NK1.1 receptor commonly found on NK cells. iNKT cells are activated as part of the early response to many infections; they differ from the major lineage of α:β T cells in recognizing CD1 molecules rather than MHC class I or MHC class II molecules (see Section 6-18). Unlike other T cells, iNKT cells require for their development a T-cell receptor interaction with CD1 molecules expressed on thymocytes and a signal through the adaptor protein SAP. iNKT cells, like γ:δ T cells, acquire a defined effector program during their development in the thymus. Therefore, these cells exhibit a memory-cell phenotype when they leave the thymus and
After 3–4 days in the medulla, CD4 and CD8 T cells upregulate SIP1 and exit the thymus into the blood blood vessel SIPSIPR1 CD4 and CD8 T cells entering the medulla are not fully mature
Fig. 8.32 Thymocyte emigration is induced by signaling through the sphingosine 1-phosphate receptor, S1PR1. CD4 and CD8 single-positive thymocytes that have successfully survived positive and negative selection are found in the medulla but are not yet fully mature. At the termination of the maturation process, which takes 3–4 days, the CD4 and CD8 single-positive thymocytes upregulate the sphingosine 1-phosphate (S1P) receptor, known as S1PR1. S1PR1 is a G-proteincoupled receptor that promotes chemotaxis of the cells toward the ligand S1P. Due to the high levels of S1P in the blood, single-positive thymocytes are induced to leave the thymus by entering the blood, where they become part of the recirculating naive T-cell population.
MOVIE 8.1 migrate to peripheral lymphoid tissues and mucosal surfaces. iNKT cells have been suggested to develop in response to ‘agonist’ signaling. Recent studies have revealed that CD1-binding lipid antigens produced by the commensal microbes in the gut are an important source of these agonist ligands, and that the composition of the gut microbiome regulates the development of iNKT cells early in life. Since agonist stimulation of immature T cells is also known to cause clonal deletion, it is not yet clear which activating interactions lead to clonal deletion in the thymus and which lead to selection of Treg cells or the nonconventional iNKT cells.