The stages of thymocyte development up to the expression of the pre-T-cell receptor—including the decision between commitment to either the α:β or the γ:δ lineage—are all independent of interactions with peptide:MHC antigens. With the successful rearrangement of α-chain genes and expression of the T-cell receptor, α:β thymocytes undergo further development that is determined by the interactions of their T-cell receptors with self peptides presented by the MHC molecules on the thymic stroma. CD4+CD8+ double-positive thymocytes whose receptors interact with self peptide:self MHC complexes on thymic cortical epithelial cells are positively selected, and will eventually mature into CD4 or CD8 single-positive cells. T cells that react too strongly with self antigens are deleted in the thymus, a process driven by bone marrow-derived antigen-presenting cells and AIRE-expressing epithelial cells in the medullary region of the thymus. The outcome of positive and negative selection is the generation of a mature conventional T-cell repertoire that is both MHC-restricted and self-tolerant. Some non-conventional T-cell lineages undergo ‘agonist’ selection following strong T-cell receptor signaling. Precisely how the recognition of self peptide:self MHC ligands by the T-cell receptor leads to either positive or negative selection remains an unsolved problem.
Summary to Chapter 8.
In this chapter we have learned about the formation of the B-cell and T-cell lineages from an uncommitted hematopoietic stem cell. The somatic gene rearrangements that generate the highly diverse repertoire of antigen receptors—immunoglobulin for B cells, and the T-cell receptor for T cells— occur in the early stages of the development of T cells and B cells from a common bone marrow-derived lymphoid progenitor. Mammalian B-cell development takes place in fetal liver and, after birth, in the bone marrow; T cells also originate from stem cells in the fetal liver or the bone marrow, but undergo most of their development in the thymus. Much of the somatic recombination machinery, including the RAG proteins that are an essential part of the V(D)J recombinase, is common to both B and T cells. In both B and T cells, gene rearrangements begin with the loci that contain D gene segments, and proceed successively at each locus. The first step in B-cell development is the rearrangement of the locus for the immunoglobulin heavy chain, and for T cells the β chain. In each case, the developing cell is allowed to proceed to the next stage of development only if the rearrangement has produced an in-frame sequence that can be translated into a protein expressed on the cell surface: either the pre-B-cell receptor or the pre-T-cell receptor. Cells that do not generate successful rearrangements for both receptor chains die by apoptosis. The course of conventional B-cell development is summarized in Fig. 8.14, and that of α:βT cells in Fig. 8.33.