Lymphoid stem cells leave the bone marrow and reach the thymus gland via the bloodstream. At this stage of development, these cells lack surface antigens that make up the TCR complex and do not express the CD4 or CD8 coreceptor (double negative). These precursors begin recombination of TCR gene segments, of which there are four: α, β, γ, and δ. Recombination begins at the δ, γ, and β loci, and if expression of the γδ-TCR is successful, commitment to the γδ–T-cell lineage results. The γδ–T cells remain double negative and leave the thymus to populate lymphoid tissue and epithelia. A portion of the γδ–T cells are generated in the thymus, with a major fraction generated in an extrathymic compartment. Alternatively, successful αβ loci recombination results in β-TCR expression, which pairs with the surrogate α-receptor and forms the pre-TCR. The pre-TCR provides ligand-independent signals that enable commitment to the αβ–T-cell lineage and CD4/CD8 coexpression (double positive). Assembly of the pre-TCR is followed by recombination at the α loci, which, if successful, generates the αβ-TCR. Ligand-dependent selection follows and is determined by double-positive cells that bind peptide-loaded MHC molecules on thymic cortical epithelia. Double-positive cells that bind MHC with sufficient affinity are selected to survive (positive selection), whereas those that do not are eliminated by apoptosis. The interaction between the TCR and MHC molecules is restricted by the specificity of the TCR and the T-cell coreceptor: CD4 restricts interaction to class II MHC and CD8 to class I MHC. Surviving double-positive cells then lose the CD4 or CD8 coreceptor not involved in MHC recognition. These single-positive cells traffic to the thymic medulla, and those that react too strongly with self-antigens presented by medullary epithelia and bone marrow–derived APCs are deleted by apoptosis (negative selection). These processes of positive and negative selection promote viable T cells capable of recognizing and responding to peptide antigen in MHC while checking those that have autoreactivity. This is a rigorous selection, and only about 2% of the double-positive cells survive. Approximately 90% to 95% of circulating T cells use the αβ-TCR and are divided into two major subpopulations, CD4+ helper T cells and CD8+ cells.
When T cells recognize their specific peptide/MHC ligand on APCs, TCR signals result in adhesion molecule changes that strengthen and prolong APC contact. During this interaction, a second costimulatory signal is provided by CD28 on T cells that bind B7 molecules on APCs, and this facilitates activation and proliferation of naïve T cells. After costimulation, activated T cells produce IL-2, which leads to T-cell proliferation and differentiation. Once primed, naïve T cells differentiate into effector cells that perform antigen-specific functions without
the need for costimulation.
Source: Cummings Otolaryngology, 6E (2015)