The AIDS virus (HIV) uses CD4 molecules (as well as chemokine receptors) to enter helper T cells (see Figure 23–17). AIDS patients are susceptible to infection by microbes that are not normally dangerous because HIV depletes helper T cells. As a result, most AIDS patients die of infection within several years of the onset of symptoms, unless they are treated with a combination of anti-HIV drugs. HIV also uses CD4 and chemokine receptors to enter macrophages, which also have both types of receptors on their surface.
T cell development begins when bone-marrow-derived lymphoid progenitor cells enter the thymus from the bloodstream. There, the cells receive a variety of signals from thymus stromal cells, epithelial cells, macrophages, and dendritic cells, which promote their stepwise development into mature thymocytes. At one step, the progenitor cells are induced to express V(D)J recombinase and begin to rearrange their TCR gene segments. Soon thereafter, the cells express both CD4 and CD8 co-receptors, and these so-called double‑positive thymocytes migrate inward and interact with thymus dendritic cells or epithelial cells expressing self peptides bound to class I and class II MHC proteins. If the TCR on the thymocyte binds with high affinity to these complexes, a strong signal will be transmitted, causing the cell to undergo apoptosis. This process, called negative selection, is an example of clonal deletion (see Figure 24–21), and it eliminates thymocytes that could potentially attack normal host cells and tissues and thereby cause an autoimmune disease if the cells were to continue to mature and leave the thymus.
If its TCR is unable to bind at all to a self-peptide–MHC complex in the thymus, the thymocyte will fail to receive the signals it needs to survive and will die of “neglect;” without the ability to recognize self-MHC proteins, a T cell would generally be of no use, as T cells can only see pathogen-derived peptides in the context of self-MHC proteins. Thymocytes that express a TCR that binds with an appropriate affinity to a self peptide bound to either a class I MHC protein (using CD8 as a co-receptor) or a class II MHC protein (using CD4 as a co-receptor) will receive an optimal signal to survive and continue to mature, a process called positive selection (Figure 24–41). As part of this maturation process, and depending on the TCR’s preference for class I or class II MHC proteins, the CD4 or CD8 co-receptor that is not needed is silenced by DNA methylation of the respective gene; this results in the development of CD4 or CD8 single‑positive thymocytes, which exit the thymus as naïve T cells and enter the recirculating pool of T cells—the CD4 cells as either helper or regulatory T cells and the CD8 cells as cytotoxic T cells.
Although naïve helper and cytotoxic T cells constantly receive survival signals in the form of self peptides bound to MHC proteins that the T cells bind weakly, a T cell is only activated to proliferate and mount an immune response if its TCR binds with high affinity to a peptide–MHC complex and receives co-stimulatory signals at the same time. Generally, this happens only when the T cell encounters an activated dendritic cell (in a peripheral lymphoid organ) that expresses an MHC protein with a foreign peptide derived from a pathogen in its binding groove. Only then will the naïve T cell proliferate and differentiate into an effector or memory T cell.