Fig. 8.29 Negative selection of thymocytes can occur in the cortex or the medulla. When the T-cell receptor (TCR) on a developing thymocyte is strongly stimulated by recognition of self peptide:self MHC complexes (red cell), the thymocyte is induced to die, a process known as negative selection. Negative selection can occur in the cortex when a CD4+CD8+ double-positive thymocyte has strong reactivity to peptide:MHC complexes found on cortical epithelial cells (left panel). Negative selection can also occur in the medulla when an immature CD4 or CD8 single-positive thymocyte receives strong T-cell receptor signaling following recognition of peptide:MHC complexes on medullary epithelial cells (middle panel) or on bone marrow-derived macrophages or dendritic cells (right panel).
AIRE expression in the thymus
Fig. 8.30 AIRE is expressed in the medulla of the thymus and promotes the expression of proteins normally expressed in peripheral tissues.
Expression of AIRE by thymic medullary cells is limited to the medullary region of the thymus, where it is expressed in a subset of epithelial-like cells. The expression of the thymic medullary epithelial marker MTS10 is shown in red. AIRE expression is shown in green by immunofluorescence, and is present in only a fraction of the medullary epithelial cells. Photograph courtesy of R.K. Chin and Y.-X. Fu.
in development. There are, however, several mechanisms operating in the periphery that can prevent mature T cells from responding to tissue-specific antigens; these are discussed in Chapter 15, when we consider the problem of autoimmune responses and their avoidance.
8-24 Negative selection is driven most efficiently by bone marrow-derived antigen-presenting cells.
As discussed above, negative selection occurs throughout thymocyte development, both in the thymic cortex and in the medulla, and so is likely to be mediated by antigen presentation by several different cell types (see Fig. 8.29). There does seem to be a hierarchy in the effectiveness of cells in mediating negative selection. At the top are bone marrow-derived dendritic cells and macrophages. These are antigen-presenting cells that also activate mature T cells in peripheral lymphoid tissues, as we shall see in Chapter 9. The self antigens presented by these cells are therefore the most important source of potential autoimmune responses, and T cells responding to such self peptides must be eliminated in the thymus.
In addition, both the thymocytes themselves and the thymic epithelial cells can cause the deletion of self-reactive cells. The medullary epithelial cells expressing AIRE, and thus presenting a wide range of self-antigens, are one population that has been shown to directly induce thymocyte negative selection. More generally, in patients undergoing bone marrow transplantation from an unrelated donor, where all the thymic macrophages and dendritic cells are of donor type, negative selection mediated by thymic epithelial cells is of critical importance in maintaining tolerance to the recipient’s own antigens.
8-25 The specificity and/or the strength of signals for negative and positive selection must differ.