Adaptive immune cells, like T cells, play a critical role in protecting our bodies against invading pathogens, a task that relies upon their ability to recognize pathogens as foreign, or ‘non-self’. This begs the question, though, of how adaptive immune cells distinguish between self and non-self. How is it that T cells know to attack and kill an invading bacterial cell while leaving our neighboring self-cells alone and unharmed? That answer to this question lies in the processes of positive and negative selection.
T cell thymic development
T-cells originate from stem cells in the bone marrow and develop in the thymus, a small lymphoid organ located between the lungs. Once in the thymus, immature T cells progress through multiple developmental stages on their road to differentiation into mature T cells capable of recognizing antigens and protecting our bodies from infection. During this period of development, T cells undergo somatic recombination to generate individual T cell clones expressing unique TCRs. These TCRs are key molecules in the identity of each T cell, as they each have the ability to bind and recognize different antigens. In general, this antigen recognition process occurs when the TCR binds to antigen being presented by other cells on MHC proteins (MHC class I in the case of CD8+ T cells, MHC class II in the case of CD4+ T cells). For example, if one of your cells were to be infected by a virus, this infected cell could present viral antigens on its surface via MHC class I molecules, and this antigen-MHC complex would act as a danger signal to the surrounding immune cells. A T cell with a compatible TCR could then bind to the antigen-MHC complex on the infected cell and kill it, thereby preventing the spread of the virus (Figure 1, top). Given the important role of the TCR in facilitating antigen recognition and cellular killing, it is vitally important that the TCRs produced by somatic recombination 1) are capable of binding MHC complexes and 2) will not recognize our own cells, which also express MHC proteins bound to normal, self-peptides. T cells, then, must walk a very fine line between recognition of that which is foreign and harmful, and that which is self and safe.
To address the necessity that T cells be capable of binding MHC complexes, T cells undergo positive selection. In this process, cells in the thymus present short pieces of proteins, called peptides, on their own MHC class I and class II molecules, allowing immature T cells to bind. If TCRs are incapable of binding, the T cell will undergo a type of cell death celled apoptosis. If, however, a T cell’s TCR successfully binds to the MHC complexes on the thymic cells, the T cell receives survival signals and is thus positively selected (Figure 1, middle). Further, this positive selection process also determines if a T cell will become a CD8+ T cell or a CD4+ T cell. Specifically, if a TCR complex binds strongly to MHC class II, the complex will send intracellular signals to induce the expression of a protein called ThPOK. This protein reduces the expression of another key protein, called Runx3, responsible for driving CD8 expression. Because low Runx3 causes low CD8, these ThPOK+, Runx3- cells become CD4+. If, however, a developing T cell does not bind strongly to MHC class II, ThPOK levels will be low and thus Runx3 levels will be high, pushing the T cell to differentiate into a CD8+ cell. In sum, the process of positive selection leads to the survival of mature CD8+ and CD4+ T cells capable of recognizing MHC complexes.
While the ability of T cells to recognizes antigen-MHC complex is vital for their ability to fight pathogens and other foreign cells, it is equally important that these T cells do not recognize and attack our own cells. This is where negative selection comes into play. As described above, developing T cells in the thymus are presented with peptides bound to MHC molecules, to which they may be able to bind. Importantly, while a moderate degree of binding leads to survival and positive selection, TCRs that bind too strongly to these MHC complexes are destined for the opposite fate (Figure 1, bottom). It is thought that, when TCRs bind too strongly to the MHC complexes in the thymus, the intracellular signaling is so strong that it actually leads to cell death, thereby eradicating immature T cell that have a high likelihood of being self-reactive and attacking our own cells.
One of the most intriguing aspects of negative selection is that it primarily occurs in the thymus, which means that T cells rely solely on the cells in the thymus to present self-peptides on MHC molecules. Because of this, it is tempting to think that negative selection will only delete T cells who show reactivity to thymic self-peptides… but what about peptide-MHC complexes specific to the stomach or the skin or the lungs? Would the T cells that survive negative selection leave the thymus only to kill cells of our other organs? Clearly, this is not the case, and the reason is attributed to a protein called autoimmune regulator, or AIRE. The role of AIRE in the thymus is to induce the expression of many proteins that are not typically expressed in thymic cells, such as proteins characteristic of the lungs. In this way, developing T cells are exposed to many peptide-MHC complexes, not just those normally expressed by thymic cells, thereby preventing autoimmunity once T cells leave the thymus.