Central Tolerance: Filtering Self-Reactive Lymphocytes Before They Leave | Visual AI Learning Guide

In the thymus, developing T cells are tested against self-peptides. Strong recognition triggers apoptosis, deleting the cell. Weaker recognition can push the cell into the regulatory lineage instead. But this filter only catches lymphocytes whose self-antigen is actually shown in the thymus. Tissue-restricted proteins often are not, so those cells survive and leave. They are the escapees that peripheral tolerance must later hold in check.

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Central tolerance is the first line of defense against self-reactivity. In the thymus, developing T cells are tested against self-peptides displayed on MHC molecules by thymic epithelial cells and dendritic cells. A T cell whose receptor binds self-peptide too strongly receives a strong signal and is eliminated by apoptosis, a process called negative selection. A weaker interaction may instead divert the cell into the regulatory T cell lineage, converting a potential threat into a suppressor. B cells undergo an analogous process in the bone marrow, where strongly self-reactive B cells can be deleted or edit their receptor through light-chain replacement.

The critical limitation is coverage. Negative selection can only remove lymphocytes that encounter their self-antigen in the thymus or bone marrow. Many tissue-restricted proteins are expressed at low levels or not at all in these organs, so lymphocytes specific for them survive and enter the circulation. Central tolerance is therefore a strong but incomplete filter, and the escapees are the raw material for autoimmunity if peripheral tolerance later fails.