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Figure 5: Negative selection of autoreactive T cells and natural Treg development. This figure schematically shows a very simplified version of negative selection that takes place in the thymus and removes auto-reactive T cells. On top, a cellular autoantigen expressed in the thymus is shown, containing both class I and class II epitopes as indicated. When developing T cells recognise these peptides, most of them will undergo negative selection as indicated below the represented antigen. These cells will die, and their differentiation will not continue (crossed-out cells). However, a small percentage of low-affinity autoreactive T cells survives negative selection. These can be both CD4 (in green) and CD8 T cells, as shown at the bottom of the figure. However, if CD4 T cells strongly recognise the autoantigen epitope, they can also differentiate into highly suppressive natural Tregs (left on the figure, Treg). When released out of the thymus, these nTregs will control the activity of autoreactive T cells, in case that these get activated “by mistake” during antigen presentation. This is possibly one of the major barriers for cancer immunotherapy, as many of these autoreactive T cells can be potential TAA-specific cytotoxic T cells.