T-cell progenitors develop along the γ:δ or the α:β T-cell lineages. Early in ontogeny, the production of γ:δ T cells predominates over α:β T cells, and these cells populate several peripheral tissues, including the skin, the intestine, and other mucosal and epithelial surfaces. These subsets predominantly develop from fetal liver, rather than bone marrow, stem cells. Later, more than 90% of thymocytes express α:β T-cell receptors. In developing thymocytes, the γ, δ, and β genes are the first to rearrange. Cells of the α:β lineage that rearrange a functional beta chain form a pre-T-cell receptor that signals thymocyte proliferation, α-chain gene rearrangement, and CD4 and CD8 expression. Most steps in T-cell development take place in the thymic cortex, whereas the medulla contains mainly mature T cells.
Positive and negative selection of T cells.
Up to the stage at which an α:β receptor is produced, T-cell development is independent of MHC proteins or antigen. From this point onward, developmental decisions in the α:β T-cell lineage depend on the interaction of the receptor with peptide:MHC ligands it encounters in the thymus, and we now consider this phase of T-cell development.
T-cell precursors committed to the α:β lineage at the DN3 stage undergo vigorous proliferation in the subcapsular region and progress to the DN4 stage. These cells then rapidly transit through an immature CD8 single-positive stage and become double-positive cells that express low levels of the T-cell receptor and both the CD4 and CD8 co-receptors as they move deeper into the thymic cortex. These double-positive cells have a life-span of only about 3–4 days unless they are rescued by engagement of their T-cell receptor. The rescue of double-positive cells from programmed cell death and their maturation into CD4 or CD8 single-positive cells is the process known as positive selection. Only about 10–30% of the T-cell receptors generated by gene rearrangement will be able to recognize self peptide:self MHC complexes and thus function in self MHC-restricted responses to foreign antigens (see Chapter 4); those that have this capability are selected for survival in the thymus. Double-positive cells also undergo negative selection: T cells whose receptors recognize self peptide:self MHC complexes too strongly undergo apoptosis, thus eliminating potentially self-reactive cells. In this section, we examine the interactions between developing double-positive thymocytes and different thymic components and discuss the mechanisms by which these interactions shape the mature T-cell repertoire.
8-19 Only thymocytes whose receptors interact with self peptide:self MHC complexes can survive and mature.