Traveling along chemical signals, thymocyte precursors migrate via blood from the bone marrow to the thymus. These cells have not yet rearranged their T cell receptor (TCR) genes and thus lack the T cell receptor (let alone CD3, CD4 or CD8); still lacking any characteristics of thymocytes, these immature T cells begin to divide furiously before individually undergoing four stages denoted double negative (DN) 1-4, named as such because the cells still lack CD4 and CD8 (CD4-CD8-). The four different DN steps — taking a total of ∼3 weeks — are described below, followed by the double-positive state (CD4+CD8+) and finally mature single-positive CD4+CD8- or CD4-CD8+ cells.
| Stage | Phenotype | Overview | ||
| DN1 | c-kit+ | CD25- | CD44high | Double-negative DN1 cells enter the thymus and proliferate as they become DN2 cells. |
| DN2 | c-kit+ | CD25+ | CD44low | TCRβ genes begin rearranging first, followed by TCR γ and δ (but not α) genes by ∼14 days. |
| DN3 | c-kit- | CD25+ | CD44- | In DN3 cells, TCR γ, δ and β rearrangement progresses. Immature thymocytes not expressing Notch proteins do not mature past DN3. At the transition from DN2 to DN3, γδ thymocytes become mature, undergoing very little more change; γδ cells frequently remain double-negative, and never become CD4+. DN3 αβ thymocytes halt proliferation, and β chains combine with a 33kD pre-Tα chain (aka gp33) and associate with CD3 to form the pre-T cell receptor (pre-TCR). The pre-TCR activates the following processes:
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| DN4 | c-kit- | CD25- | CD44- | The DN4 state occurs quickly after β rearrangement completes in DN3 cells. CD4 and CD8 coreceptors begin expression, leading to the double-positive state (CD4+CD8+) |
| DP | CD4+ | CD8+ | The double-positive state (DP) involves rapid proliferation. This leads to a large population of T cell clones with identical TCR β chain rearrangements. Once proliferation stops, RAG-2 expression is activated and TCR α chain rearrangement occurs. This leads to tremendous diversity, as each TCR β chain rearrangement is now bound to a unique α chain rearrangement. | |
| CD4+CD8-/CD4-CD8+ | DP cells proceed through thymic exclusion (described below), and surviving thymocytes expressing the αβ TCR-CD3 complex mature into single-positive CD4 or CD8 cells. | |||
Thymic selection is a two-step process: positive selection, which induces apoptosis in thymocytes whose TCR cannot bind self MHC molecules; and negative selection, which induces apoptosis in thymocytes which bind self MHC molecules too well or in presence of a self peptide. Positive selection results in MHC restriction, and negative selection results in self-tolerance (meaning the thymocytes will not attack healthy self cells).
| Selection | Overview |
| Positive | Positive selection ensures the T cell only reacts to self MHC (MHC restriction) and takes place in the cortical region of the thymus, with immature thymocytes binding (or not) to MHC molecules on cortical epithelial cells. Upon binding to the MHC molecule, the thymocyte receives a protective signal that prevents apoptosis; if the thymocyte does not bind an MHC molecule, it proceeds with apoptosis. |
| Negative | Occurring after positive selection, negative selection ensures the T cell is does not react to self peptides. Dendritic cells and macrophages bearing Class I and II MHC molecules interact with thymocytes that bind self-antigen-MHC complexes or MHC complexes alone. Binding leads to apoptosis. |
There are two proposed models as to how CD4+CD8+ cells mature into CD4+CD8- or CD4-CD8+ cells: the instructive model and the stochastic model. Neither model has been definitely proven nor disproven. The instructive model postulates that double-positive cells interact with either a Class I or a Class II MHC molecule, and are somehow signaled to differentiate into either CD4 or CD8 cells. The schotastic model postulates that repression of CD4 or CD8 is random and has nothing to do with TCR specificity. Only thymocytes whose TCR and coreceptor bind the same MHC molecule continue to mature.
| Next Steps | Study T cell activation and proliferation and differentiation. |
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