<P> This process does not remove thymocytes that may cause autoimmunity . The potentially autoimmune cells are removed by the process of negative selection, which occurs in the thymic medulla (discussed below). </P> <P> Negative selection removes thymocytes that are capable of strongly binding with "self" MHC peptides . Thymocytes that survive positive selection migrate towards the boundary of the cortex and medulla in the thymus . While in the medulla, they are again presented with a self - antigen presented on the MHC complex of medullary thymic epithelial cells (mTECs). mTECs must be AIRE to properly express self - antigens from all tissues of the body on their MHC class I peptides . Some mTECs are phagocytosed by thymic dendritic cells; this allows for presentation of self - antigens on MHC class II molecules (positively selected CD4 cells must interact with MHC class II molecules, thus APCs, which possess MHC class II, must be present for CD4 T - cell negative selection). Thymocytes that interact too strongly with the self - antigen receive an apoptotic signal that leads to cell death . However, some of these cells are selected to become Treg cells . The remaining cells exit the thymus as immature naïve T cells (also known as recent thymic emigrants). This process is an important component of central tolerance and serves to prevent the formation of self - reactive T cells that are capable of inducing autoimmune diseases in the host . </P> <P> In summary, β - selection is the first checkpoint, where the T cells that are able to form a functional pre-TCR with an invariant alpha chain and a functional beta chain are allowed to continue development in the thymus . Next, positive selection checks that T cells have successfully rearranged their TCRα locus and are capable of recognizing peptide - MHC complexes with appropriate affinity . Negative selection in the medulla then obliterates T cells that bind too strongly to self - antigens expressed on MHC molecules . These selection processes allow for tolerance of self by the immune system . Typical T cells that leave the thymus (via the corticomedullarly junction) are self - restricted, self - tolerant, and singly positive . </P> <P> Activation of CD4 T cells occurs through the simultaneous engagement of the T - cell receptor and a co-stimulatory molecule (like CD28, or ICOS) on the T cell by the major histocompatibility complex (MHCII) peptide and co-stimulatory molecules on the APC . Both are required for production of an effective immune response; in the absence of co-stimulation, T cell receptor signalling alone results in anergy . The signalling pathways downstream from co-stimulatory molecules usually engages the PI3K pathway generating PIP3 at the plasma membrane and recruiting PH domain containing signaling molecules like PDK1 that are essential for the activation of PKCθ, and eventual IL - 2 production . Optimal CD8 T cell response relies on CD4 signalling . CD4 cells are useful in the initial antigenic activation of naïve CD8 T cells, and sustaining memory CD8 T cells in the aftermath of an acute infection . Therefore, activation of CD4 T cells can be beneficial to the action of CD8 T cells . </P>

What signal does a t cell require in order to divide